Substituted Heterocyclyl Derivatives as CDK Inhibitors

ABSTRACT

The present invention provides substituted heterocyclylderivatives of formula (I), which are therapeutically useful, particularly as selective transcriptional CDK inhibitors including CDK7, CDK9, CDK12, CDK13 and CDK18, more particularly transcriptional CDK7 inhibitors. These compounds are useful in the treatment and prevention of diseases and/or disorders associated with selective transcriptional CDKs in a mammal. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the substituted heterocyclyl derivatives of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.

This application claims the benefit of Indian provisional applicationnumbers 2803/CHE/2015, filed on Jun. 4, 2015 and 6214/CHE/2015, filed onNov. 18, 2015; the specifications of which are hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

This invention pertains to compounds which inhibit the activity ofselective transcriptional cyclin dependent kinases (CDKs) includingCDK7, CDK9, CDK12, CDK13 and CDK18, more particularly transcriptionalcyclin dependent kinase-7 (CDK7). The invention also providespharmaceutically acceptable compositions comprising compounds of thepresent invention and methods of using said compositions in thetreatment of diseases or disorder associated with selectivetranscriptional CDKs.

BACKGROUND OF THE INVENTION

One of the most important and fundamental processes in biology is thedivision of cells mediated by the cell cycle. This process ensures thecontrolled production of subsequent generations of cells with definedbiological function. It is a highly regulated phenomenon and responds toa complex set of cellular signals both within the cell and from externalsources. A complex network of tumor promoting and suppressing geneproducts are key components of this cellular signalling process.Over-expression of tumor-promoting components or the subsequent loss ofthe tumor-suppressing products will lead to unregulated cellularproliferation and the generation of tumors (Pardee, Science 246:603-608,1989).

Kinases are important cellular enzymes that perform essential cellularfunctions such as regulating cell division and proliferation, and alsoappear to play a decisive role in many disease states that arecharacterized by uncontrolled proliferation and differentiation ofcells. These disease states encompass a variety of cell types andmaladies such as cancer, atherosclerosis, restenosis and otherproliferative disorders (Kris M G et al., JAMA 290 (16): 2149-58, 2003).

Cyclin-dependent kinases (CDKs) are relatively small proteins, withmolecular weights ranging from 34 to 40 kDa, and contain little morethan the kinase domain. CDK binds a regulatory protein called a cyclin.Without cyclin, CDK has little kinase activity; only the cyclin-CDKcomplex is an active kinase. CDKs phosphorylate their substrates onserines and threonines, so they are serine-threonine kinases (Morgan, D.O., Cell Division, 2:27, 2007).

The members of the cyclin-dependent kinase (CDK) family play criticalregulatory roles in cell proliferation. There are currently 20 knownmammalian CDKs. While CDK7-13 and 18 have been linked to transcription,only CDK1, 2, 4 and 6 show demonstrable association with the cell cycle.Unique among the mammalian CDKs, CDK7 has consolidated kinaseactivities, regulating both the cell cycle and transcription. In thecytosol, CDK7 exists as a heterotrimeric complex and is believed tofunction as a CDK1/2-activating kinase (CAK), whereby phosphorylation ofconserved residues in CDK1/2 by CDK7 is required for full catalytic CDKactivity and cell cycle progression (Desai et al., Mol. Cell Biol. 15,345-350, 1995).

CDK7, which complexes with cyclin H and MAT1, phosphorylates the cellcycle CDKs in the activation of T-loop, to promote their activities(Fisher et al., Cell., August 26; 78(4): 713-24, 1994). As such, it hasbeen proposed that inhibiting CDK7 would provide a potent means ofinhibiting cell cycle progression, which may be especially relevantgiven that there is compelling evidence from gene knockout studies inmice for lack of an absolute requirement for CDK2, CDK4 and CDK6 for thecell cycle, at least in most cell types (Malumbres et al., Nature CellBiology, 11, 1275-1276, 2009), whilst different tumors appear to requiresome, but be independent of other interphase CDKs (CDK2, CDK4, CDK6).Recent genetic and biochemical studies have confirmed the importance ofCDK7 for cell cycle progression (Larochelle et al., Mol Cell., March 23;25(6):839-50. 2007; Ganuza et al., EMBO J., May 30; 31(11): 2498-510,2012).

Cyclin-dependent kinase 7 (CDK7) activates cell cycle CDKs and is amember of the general Transcription factor II Human (TFIIH). CDK7 alsoplays a role in transcription and possibly in DNA repair. The trimericCak complex CDK7/CyclinH/MAT1 is also a component of TFIIH, the generaltranscription/DNA repair factor IIH (Morgan, D. O., Annu. Rev. Cell Dev.Biol. 13, 261-91, 1997). As a TFIIH subunit, CDK7 phosphorylates the CTD(Carboxy-Terminal-Domain) of the largest subunit of RNA polymerase II(pol II). The CTD of mammalian pol II consists of 52 heptad repeats withthe consensus sequence ¹YSPTSPS⁷ and the phosphorylation status of theSer residues at positions 2 and 5 has been shown to be important in theactivation of RNAP-II indicating that it is likely to have a crucialrole in the function of the CTD. CDK7, which primarily phosphorylatesSer-5 (PS5) of RNAP-II at the promoter as part of transcriptionalinitiation (Gomes et al., Genes Dev. 2006 Mar. 1; 20(5):601-12, 2006),in contrast with CDK9, which phosphorylates both Ser-2 and Ser-5 of theCTD heptad (Pinhero et al., Eur. J. Biochem., 271, pp. 1004-1014, 2004).

In addition to CDK7, other CDKs have been reported to phosphorylate andregulate RNA pol (II) CTD. The other CDKs include, Cdk9/Cyclin T1 or T2that constitute the active form of the positive transcription elongationfactor (P-TEFb) (Peterlin and Price, Mol Cell., August 4; 23(3):297-305,2006) and Cdk12/Cyclin K and Cdk13/Cyclin K as the latestmembers of RNAPII CTD kinases (Bartkowiak et al., Genes Dev., October15; 24(20):2303-16, 2010; Blazek et al., Genes Dev. October 15;25(20):2158-72, 2011).

Disruption of RNAP II CTD phosphorylation has been shown topreferentially effect proteins with short half-lives, including those ofthe anti-apoptotic BCL-2 family. (Konig et al., Blood, 1, 4307-4312,1997; The transcriptional non-selective cyclin-dependent kinaseinhibitor flavopiridol induces apoptosis in multiple myeloma cellsthrough transcriptional repression and down-regulation of Mcl-1; (Gojoet al., Clin. Cancer Res. 8, 3527-3538, 2002).

This suggests that the CDK7 enzyme complexes are involved in multiplefunctions in the cell: cell cycle control, transcription regulation andDNA repair. It is surprising to find one kinase involved in such diversecellular processes, some of which are even mutually exclusive. It alsois puzzling that multiple attempts to find cell cycle dependent changesin CDK7 kinase activity remained unsuccessful. This is unexpected sinceactivity and phosphorylation state of its substrate, CDCl₂, fluctuateduring the cell cycle. In fact, it is shown that cdk7 activity isrequired for the activation of bothCdc2/Cyclin A and Cdc2/Cyclin Bcomplexes, and for cell division. (Larochelle, S. et al. Genes Dev12,370-81, 1998). Indeed, flavopiridol, a non-selective pan-CDKinhibitor that targets CTD kinases, has demonstrated efficacy for thetreatment of chronic lymphocytic leukemia (CLL), but suffers from a poortoxicity profile (Lin et al., J. Clin. Oncol. 27, 6012-6018, 2009;Christian et al., Clin. Lymphoma Myeloma, 9, Suppl. 3, S179-S185, 2009).

In-vitro studies revealed substrate preferences for the different CDK7complexes, indicating that CDK7 may form different complexes withdifferent substrate specificity and presumably different in-vivofunctions (Frit, P. et al., Biochimie 81, 27-38, 1999; Schutz, P. et al.Cell 102, 599-607, 2000).

Thus in view of the role transcriptional CDKs play in the regulation ofcell cycle, there is a need of compounds to treat diseases and/ordisorder associated with selective transcriptional CDKs including CDK7,CDK9, CDK12, CDK13 and CDK18; more particularly CDK7. It is, therefore,an object of this invention to provide compounds useful in the treatmentand/or prevention or amelioration of such diseases and/or disorder.

SUMMARY OF THE INVENTION

Provided herein are substituted heterocyclyl derivatives andpharmaceutical compositions thereof, which are capable of suppressingand/or inhibiting cyclin dependent kinase-7 signalling pathway.

In one aspect of the present invention, it comprises compounds offormula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

ring A is cycloalkyl, aryl, heteroaryl or heterocyclyl;

ring B is aryl, cycloalkyl, heterocyclyl or absent;

R₁ is hydrogen or alkyl;

R₂ is hydrogen, alkyl or cycloalkyl;

R₃ is hydrogen, alkyl or heteroaryl;

alternatively, R₂ together with R₁ or R₃ along with the ring atoms towhich they are attached forms a 5-7 membered ring;

R₄ at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro,cyano or haloalkyl;

R₅ is

wherein R₅′ is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or—(CH₂)₁₋₃—NR_(a)R_(b); R₅″ is H or alkyl;

R_(a) and R_(b) are each independently hydrogen, alkyl, alkoxy oralkoxyalkyl; alternatively, R_(a) and R_(b) together with the nitrogenatom to which they are attached form an optionally substituted ringcontaining 0-2 additional heteroatoms independently selected from N, Oor S; wherein the optional substituent is one or more halo, alkyl, acyl,hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, —COOH or—COO-alkyl;

R₆ at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro,cyano or haloalkyl;

L₁ is *—CR_(c)R_(d)—C(O)—, *—NR_(c)C(O)— or absent; wherein * is pointof attachment with ring A;

R_(c) and R_(d) independently are hydrogen, alkyl or haloalkyl;alternatively, R_(c) and R_(d) together with the carbon to which theyare attached form a cycloalkyl ring;

R_(c) is hydrogen or alkyl;

L₂ is —C(O)NH—, —C(O)O— or absent;

m is 0, 1 or 2;

p is 0 or 1; and

q is 0 to 3.

In yet another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and at least one pharmaceutically acceptableexcipient (such as a pharmaceutically acceptable carrier or diluent).

In yet another aspect, the present invention relates to the preparationof compounds of formula (I).

In yet another aspect of the present invention, provided herein aresubstituted heterocyclyl derivatives of formula (I), which are capableof inhibiting CDK7 and therapeutic use thereof.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in artto which the subject matter herein belongs. As used in the specificationand the appended claims, unless specified to the contrary, the followingterms have the meaning indicated in order to facilitate theunderstanding of the present invention.

As used herein, unless otherwise defined the term “alkyl” alone or incombination with other term(s) means saturated aliphatic hydrocarbonchains, including C₁-C₁₀ straight or C₃-C₁₀ branched alkyl groups.Examples of “alkyl” include but are not limited to methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl orneopentyl and the like.

As used herein, the term “halo” or “halogen” alone or in combinationwith other term(s) means fluorine, chlorine, bromine or iodine.

As used herein, the term “haloalkyl” means alkyl substituted with one ormore halogen atoms, wherein the alkyl groups are as defined above. Theterm “halo” is used herein interchangeably with the term “halogen” meansF, Cl, Br or I. Examples of “haloalkyl” include but are not limited tofluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl,2,2,2-trifluoroethyl and the like.

As used herein, the term “hydroxy” or “hydroxyl” alone or in combinationwith other term(s) means —OH.

As used herein, the term “alkoxy” refers to the group alkyl-O— or—O-alkyl, where alkyl groups are as defined above. Exemplary alkoxy-groups include but are not limited to methoxy, ethoxy, n-propoxy,n-butoxy, t-butoxy and the like. An alkoxy group can be unsubstituted orsubstituted with one or more suitable groups.

As used herein, the term “alkoxyalkyl” refers to the groupalkyl-O-alkyl-, wherein alkyl and alkoxy groups are as defined above.Exemplary alkoxyalkyl- groups include but are not limited tomethoxymethyl, ethoxymethyl, methoxyethyl, isopropoxymethyl and thelike.

As used herein, the term “cyano” refers to —CN; and the term“cyanoalkyl” refers to alkyl substituted with —CN; wherein the alkylgroups are as defined above.

As used herein, the term “amino” refers to —NH₂;

As used herein, the term “nitro” refers to —NO₂;

As used herein, the term “acyl” refers to the group —C(O)-alkyl, whereinalkyl groups are as defined above. Exemplary alkoxy- groups include butare not limited to acetyl, propanoyl and acrylyl. An alkoxy group can beunsubstituted or substituted with one or more suitable groups.

As used herein the term “cycloalkyl” alone or in combination with otherterm(s) means —C₃-C₁₀ saturated cyclic hydrocarbon ring. A cycloalkylmay be a single ring, which typically contains from 3 to 7 carbon ringatoms. Examples of single-ring cycloalkyls include but are not limitedto cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and thelike. A cycloalkyl may alternatively be polycyclic or contain more thanone ring. Examples of polycyclic cycloalkyls include bridged, fused andspirocyclyls and the like.

As used herein, the term “aryl” is optionally substituted monocyclic,bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14carbon atoms. Examples of a C₆-C₁₄ aryl group include, but are notlimited to phenyl, naphthyl, anthryl, tetrahydronaphthyl, fluorenyl,indanyl, biphenylenyl and acenaphthyl. Aryl group which can beunsubstituted or substituted with one or more suitable groups.

The term “heterocycloalkyl” refers to a non-aromatic, saturated orpartially saturated monocyclic or polycyclic ring system of 3 to 15members having at least one heteroatom or heterogroup selected from O,N, S, S(O), S(O)₂, NH or C(O) with the remaining ring atoms beingindependently selected from the group consisting of carbon, oxygen,nitrogen and sulfur. A monocyclic heterocycloalkyl may typically contain4 to 7 ring atoms. Examples of “Heterocycloalkyl” include, but are notlimited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl,oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl,piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl,oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl,azepanyl and N-oxides thereof. Attachment of a heterocycloalkylsubstituent can occur via either a carbon atom or a heteroatom. Aheterocycloalkyl group can be optionally substituted with one or moresuitable groups by one or more aforesaid groups.

As used herein, the term “heteroaryl” alone or in combination with otherterm(s) means a completely unsaturated ring system containing a total of5 to 14 ring atoms. At least one of the ring atoms is a heteroatom(i.e., oxygen, nitrogen, or sulfur), with the remaining ringatoms/groups being independently selected from the group consisting ofcarbon, oxygen, nitrogen or sulfur. A heteroaryl may be a single-ring(monocyclic) or polycyclic ring system. Examples of “heteroaryl” includebut are not limited to pyridyl, indolyl, benzimidazolyl, benzothiazolyland the like.

As used herein, the term “heterocyclyl” alone or in combination withother term(s) includes both “heterocycloalkyl” and “heteroaryl” groupswhich are as defined above.

The term “heteroatom” as used herein designates a sulfur, nitrogen oroxygen atom.

As used in the above definitions, the term “optionally substituted” or“substituted” or “optionally substituted with suitable groups” refers toreplacement of one or more hydrogen radicals in a given structure with aradical of a specified substituent including, but not limited to: halo,alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio,alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl,arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl,alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl,haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino,alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl,carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl,aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonicacid, aryl and heteroaryl. It is understood that the substituent may befurther substituted.

As used herein, the term ‘compound(s)’ comprises the compounds disclosedin the present invention.

As used herein, the term “comprise” or “comprising” is generally used inthe sense of include, that is to say permitting the presence of one ormore features or components.

As used herein, the term “or” means “and/or” unless stated otherwise.

As used herein, the term “including” as well as other forms, such as“include”, “includes” and “included” is not limiting.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

As used herein, the term “treat”, “treating” and “treatment” refer to amethod of alleviating or abrogating a disease and/or its attendantsymptoms.

As used herein, the term “prevent”, “preventing” and “prevention” referto a method of preventing the onset of a disease and/or its attendantsymptoms or barring a subject from acquiring a disease. As used herein,“prevent”, “preventing” and “prevention” also include delaying the onsetof a disease and/or its attendant symptoms and reducing a subject's riskof acquiring a disease.

As used herein, the term “therapeutically effective amount” refers tothat amount of the compound being administered sufficient to preventdevelopment of or alleviate to some extent one or more of the symptomsof the condition or disorder being treated.

“Pharmaceutically acceptable” means that, which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary as well as human pharmaceutical use.

The term “stereoisomers” refers to any enantiomers, diastereoisomers, orgeometrical isomers of the compounds of Formula (I), (IA), (IB), (IC),(ID), (IE), (IF) and (IG), wherever they are chiral or when they bearone or more double bonds. When the compounds of the formula (I), (IA),(IB), (IC), (ID), (IE), (IF) and (IG) are chiral, they can exist inracemic or in optically active form. It should be understood that theinvention encompasses all stereochemical isomeric forms, includingdiastereomeric, enantiomeric and epimeric forms, as well as d-isomersand l-isomers and mixtures thereof. Individual stereoisomers ofcompounds can be prepared synthetically from commercially availablestarting materials which contain chiral centers or by preparation ofmixtures of enantiomeric products followed by separation such asconversion to a mixture of diastereomers followed by separation orrecrystallization, chromatographic techniques, direct separation ofenantiomers on chiral chromatographic columns, or any other appropriatemethod known in the art. Starting compounds of particularstereochemistry are either commercially available or can be made andresolved by techniques known in the art.

Additionally, the compounds of the present invention may exist asgeometric isomers. The present invention includes all cis, trans, syn,anti, entgegen (E) and zusammen (Z) isomers as well as the appropriatemixtures thereof.

The present invention provides substituted heterocyclylderivatives offormula (I), which are useful for the inhibition of CDK7.

The present invention further provides pharmaceutical compositionscomprising the said substituted heterocyclyl compounds of formula (I)and their derivatives as therapeutic agents.

In first embodiment, the present invention provides compounds of formula(I),

or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

ring A is cycloalkyl, aryl, heteroaryl or heterocyclyl;

ring B is aryl, cycloalkyl, heterocyclyl or absent;

R₁ is hydrogen or alkyl;

R₂ is hydrogen, alkyl or cycloalkyl;

R₃ is hydrogen, alkyl or heteroaryl;

alternatively, R₂ together with R₁ or R₃ along with the ring atoms towhich they are attached forms a 5-7 membered ring;

R₄ at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro,cyano or haloalkyl;

R₅ is

wherein R₅′ is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or—(CH₂)₁₋₃—NR_(a)R_(b);

R₅″ is H or alkyl;

R_(a) and R_(b) are each independently hydrogen, alkyl, alkoxy oralkoxyalkyl; alternatively, R_(a) and R_(b) together with the nitrogenatom to which they are attached form an optionally substituted ringcontaining 0-2 additional heteroatoms independently selected from N, Oor S; wherein the optional substituent is one or more halo, alkyl, acyl,hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, —COOH or—COO-alkyl;

R₆ at each occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro,cyano or haloalkyl;

L₁ is *—CR_(c)R_(d)—C(O)—, *—NR_(c)C(O)— or absent; wherein * is pointof attachment with ring A;

R_(c) and R_(d) independently are hydrogen, alkyl or haloalkyl;alternatively, R_(c) and R_(d) together with the carbon to which theyare attached form a cycloalkyl ring;

R_(c) is hydrogen or alkyl;

L₂ is —C(O)NH—, —C(O)O— or absent;

m is 0, 1 or 2;

p is 0 or 1; and

q is 0 to 3.

In another embodiment of the present invention, it provides compounds offormula (IA),

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;wherein,

ring A is cycloalkyl, aryl, heteroaryl or heterocyclyl;

ring B is aryl, cycloalkyl, heterocyclyl or absent;

R₁ is hydrogen or alkyl;

R₂ is hydrogen, alkyl or cycloalkyl;

R₃ is hydrogen, alkyl or heteroaryl;

alternatively, R₂ together with R₁ or R₃ along with the ring atoms towhich they are attached forms a 5-7 membered ring;

R₄ at each occurrence is halo, alkyl, hydroxy or alkoxy;

R₅ is

wherein R₅′ is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or—(CH₂)₁₋₃—NR_(a)R_(b); R₅″ is H or alkyl;

R_(a) and R_(b) are each independently hydrogen or alkyl; alternatively,R_(a) and R_(b) together with the nitrogen atom to which they areattached form an optionally substituted ring containing 0-2 additionalheteroatoms independently selected from N, O or S; wherein the optionalsubstituent is one or more halo, alkyl, hydroxy, haloalkyl or alkoxy;

L₁ is *—CR_(c)R_(d)—C(O)—, *—NR_(c)C(O)— or absent; wherein * is pointof attachment with ring A;

R_(c) and R_(d) independently are hydrogen, alkyl or haloalkyl;alternatively, R_(c) and R_(d) together with the carbon to which theyare attached form a cycloalkyl ring;

R_(c) is hydrogen or alkyl;

L₂ is —C(O)NH—, —C(O)O— or absent;

m is 0, 1 or 2; and

p is 0 or 1.

In another embodiment of the present invention, it provides compounds offormula (IA), or a pharmaceutically acceptable salt thereof or astereoisomer thereof, wherein, ring A is cycloalkyl, aryl, heteroaryl orheterocyclyl;

ring B is aryl, cycloalkyl, heterocyclyl or absent;

R₁ is hydrogen or alkyl;

R₂ is hydrogen, alkyl or cycloalkyl;

R₃ is hydrogen, alkyl or heteroaryl;

alternatively, R₂ together with R₁ or R₃ along with the ring atoms towhich they are attached forms a 5-7 membered ring;

R₄ at each occurrence is halo, alkyl, hydroxy or alkoxy;

R₅ is —(NH)_(p)—S(O)₂—CH═CH₂, —NH—CH₂—CH═CH—C(O)—NR_(a)R_(b),

wherein R₅′ is hydrogen, halo, alkyl, alkoxyalkyl or —CH₂—NR_(a)R_(b);R₅″ is H or alkyl;

R_(a) and R_(b) are each independently hydrogen or alkyl; alternatively,R_(a) and R_(b) together with the Nitrogen to which they are attachedform an optionally substituted ring containing 0-2 additionalheteroatoms independently selected from N, O or S; wherein the optionalsubstituent is one or more halo, alkyl, hydroxy, haloalkyl or alkoxy;

L₁ is *—CR_(c)R_(d)—C(O)—, *—NR_(c)C(O)— or absent; wherein * is pointof attachment with ring A;

R_(c) and R_(d) independently are hydrogen, alkyl or haloalkyl;alternatively, R_(c) and R_(d) together with the carbon to which theyare attached form a cycloalkyl ring;

R_(c) is hydrogen or alkyl;

L₂ is —C(O)NH—, —C(O)O— or absent;

m is 0, 1 or 2; and

p is 0 or 1.

In another embodiment of the present invention, it provides compounds offormula (IB),

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;

wherein, ring B, L₁, L₂, R₂, R₃, R₄, R₅, R₆, m and q are same as definedin compounds of formula (I).

In yet another embodiment of the present invention, it providescompounds of formula (IC),

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;

wherein, ring A, ring B, L₁, R₂, R₃, R₄, R₅, R₆, m and q are same asdefined in compounds of formula (I).

In yet another embodiment of the present invention, it providescompounds of formula

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;

wherein, ring B, L₁, R₂, R₃, R₄, R₅, R₆, m and q are same as defined incompounds of formula (I).

In yet another embodiment of the present invention, it providescompounds of formula

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;wherein, L₁ is *—CR_(c)R_(d)—C(O)— or *—NR_(c)C(O)—; wherein * is pointof attachment with phenyl; R₃, R₄, R₅ and m are same as defined incompounds of formula (I).

In yet another embodiment of the present invention, it providescompounds of formula (IF),

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;wherein, L₁ is *—CR_(c)R_(d)—C(O)— or *—NR_(c)C(O)—; wherein * is pointof attachment with phenyl; R₃, R₄, R₅ and m are same as defined incompounds of formula (I).

In yet another embodiment of the present invention, it providescompounds of formula (IG),

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof;wherein, ring A, L₁, R₂, R₃, R₄, R₅ and m are same as defined incompounds of formula (I).

The embodiments below are illustrative of the present invention and arenot intended to limit the claims to the specific embodimentsexemplified.

According to one embodiment, specifically provided are compounds offormula (I), wherein ring A is aryl; preferably the said aryl is phenyl.

According to another embodiment, specifically provided are compounds offormula (I), wherein ring B is aryl; preferably the said aryl is phenyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein ring B is heterocyclyl; preferably the saidheterocylcyl is piperidinyl, pyridinyl, piperazinyl, pyrazolyl,morpholinyl, indoninyl or pyrrolidinyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein ring B is absent.

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein ring B and L₂ are absent so that R₅ is directlylinked to ring A.

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein L₁ is *—CR_(c)R_(d)—C(O)— wherein * is the pointof attachment with ring A.

According to the preceding embodiment, specifically provided arecompounds of formula (I), wherein R_(c) and R_(d) are independentlyhydrogen or alkyl, wherein the said alkyl is methyl, ethyl or isopropyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein L₂ is *—C(O)NH—, *—C(O)O—, or absent; wherein *is point of attachment with ring B.

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein when L₁ is present, L₂ is absent.

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein R₂ is alkyl or cycloalkyl; preferably the saidalkyl is ethyl and the said cycloalkyl is cyclopropyl, cyclobutyl orcyclopentyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein R₃ is hydrogen and alkyl; wherein the said alkylis methyl.

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein R₄ is halo; preferably the said halo is fluoro.

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein m is 0 or 1.

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein R₅ is

wherein R₅′ is hydrogen or —CH₂—NR_(a)R_(b).

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein R₅ is

when R₅ is attached to hetero atom of ring B; R₅′ is hydrogen or—CH₂—NR_(a)R_(b).

According to the preceding two embodiments, specifically provided arecompounds of formula (I), wherein the said R_(a) and R_(b) are eachindependently hydrogen or alkyl; preferably the said alkyl is methyl.

According to the preceding embodiment, specifically provided arecompounds of formula (I), wherein the said R_(a) and R_(b) together withthe nitrogen to which they are attached form an optionally substitutedring containing 0-2 additional heteroatoms independently selected fromN, O or S; wherein the optional substituent is one or more halo,hydroxy, haloalkyl or alkoxy.

According to yet another embodiment, specifically provided are compoundsof formula (I), wherein n is 1 or 2.

In certain embodiments of formula (I), ring A is aryl or heteroaryl; inanother embodiment, the said aryl is phenyl.

In certain embodiments of formula (I), ring A is meta-substituted withrespect to L₁ and L₂.

In certain embodiments of formula (I), ring B is monocyclic or bicycliccycloalkyl, aryl, heterocycloalkyl or heteroaryl.

In certain embodiments of formula (I), ring B is heterocyclyl; inanother embodiment the said heterocylcyl is piperidinyl,pyridinyl,1,2,3,6-tetrahydropyridinyl, piperazinyl, pyrazinyl,pyrazolyl, morpholinyl, indolinyl or pyrrolidinyl.

In certain embodiments of formula (I), ring B is absent.

In certain embodiments of formula (I), wherein ring B and L₂ are absentso that R₅ is directly linked to ring A.

In certain embodiments of formula (I), R₂ is cycloalkyl; in anotherembodiment, the said cycloalkyl is cyclopropyl, cyclobutyl orcyclopentyl.

In certain embodiments of formula (I), R₂ and R₁ together with the atomsto which they are attached form a 5 or 6 membered ring.

In certain embodiments of formula (I), R₂ and R₃ together with the atomsto which they are attached form a 5 or 6 membered ring.

In certain embodiments of formula (I), R₂ and R₃ together with the atomsto which they are attached form a 6 membered aromatic ring.

In certain embodiments of formula (I), R₅ is,

wherein R₅′ and R₅″ are as defined in formula (I).

In certain embodiments of formula (I), R₅ is,

wherein R₅′ and R₅″ are as defined in formula (I).

In certain embodiments of formula (I), R₅ is

wherein R₅′ and R₅″ are as defined in formula (I).

In certain embodiments of formula (I), R₅ is

wherein R₅′ is hydrogen, halo, alkyl, alkoxy or alkoxyalkyl; and R₅″ isH or alkyl.

In certain embodiments of formula (I), R₅ is

wherein R₅′ is —CH₂—NR_(a)R_(b); R₅″ is H or alkyl; R_(a) and R_(b) areeach independently hydrogen, alkyl, alkoxy or alkoxyalkyl.

In certain embodiments of formula (I), R₅ is

wherein R₅′ is —CH₂—NR_(a)R_(b); R₅″ is H or alkyl; R_(a) and R_(b)together with the nitrogen atom to which they are attached form anoptionally substituted 4-7 membered heterocyclyl ring containing 0-2additional heteroatoms independently selected from N, O or S; whereinthe optional substituent is one or more halo, alkyl, acyl, hydroxy,cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, —COOH or —COO-alkyl.

In certain embodiments of formula (I), R₅ is

wherein p, R_(a) and R_(b) are as defined in formula (I).

In certain embodiments of formula (I), R₅ is,

wherein

is a point of attachment.

In certain embodiments of formula (I), R₅′ is —(CH₂)₁₋₃—NR_(a)R_(b);wherein R_(a) and R_(b) are as defined in formula (I).

In certain embodiments of formula (I), R_(a) and R_(b) together with thenitrogen atom to which they are attached form an optionally substitutedheterocyclic ring having 0-2 additional heteroatoms selected from O, Sor N; wherein the optional substituent is one or more halo, alkyl, acyl,hydroxy, cyano, cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, —COOH or—COO-alkyl.

In certain embodiments of formula (I), L₁ is *—CR_(c)R_(d)—C(O)—;wherein * is the point of attachment with ring A; and R_(c) and R_(d)are as defined in claim 1.

In certain embodiments of formula (I), L₂ is —C(O)NH— or —C(O)O—.

In certain embodiments of formula (I), L₂ is *—C(O)NH— or *—C(O)O—;wherein * is the point of attachment with ring B.

In certain embodiments of formula (I), when L₁ is —CR_(c)R_(d)—C(O)— or—NR_(c)C(O)—, L_(z) is absent.

In certain embodiments, the present invention provides a compoundselected from the group consisting of:

Compound No. IUPAC name 1.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 2.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide (Isomer-1 of compound-1);3.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide (Isomer-2 of compound-1);4.(E)-N-(5′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2′-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 5.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-4′-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 6.(E)-N-(3′-(1-((5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 7.(E)-N-(3′-(2-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 8.(E)-4-(dimethylamino)-N-(3′-(1-((5-ethyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)but-2-enamide; 9.(E)-N-(3′-(1-((5-(tert-butyl)-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 10.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide; 11.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide (Isomer-1 ofcompound-10); 12.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide (Isomer-2 ofcompound-10); 13.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxobutan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 14.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 15.(E)-N-(3′-(1-((5-cyclobutyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 16.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)-4-(dimethylamino)but-2-enamide; 17.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 18.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide; 19.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)acrylamide; 20.N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide; 21.N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide (Isomer-1 of compound-20); 22.N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide (Isomer-2 of compound-20); 23.N-(5′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2′,3-difluoro-[1,1′-biphenyl]-4-yl)acrylamide; 24.N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)acrylamide; 25.2-(4′-acrylamido-3′-fluoro-[1,1′-biphenyl]-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-methylbutanamide; 26.2-(3-(5-acrylamidopyridin-2-yl)phenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)butanamide; 27.2-(4′-acrylamido-3′-fluoro-[1,1′-biphenyl]-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)butanamide; 28.(E)-N-(3′-(1-((5-cyclopentyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 29.(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)indolin-5-yl)phenyl)propanamide; 30.N-(3′-(1-((5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide; 31.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxobutan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 32.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(diethylamino)but-2-enamide; 33.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(pyrrolidin-1-yl)but-2-enamide; 34.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-morpholinobut-2-enamide; 35.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)-4-morpholinobut-2-enamide; 36.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-3-yl)-4-(dimethylamino)but-2-enamide; 37.(E)-4-((6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)amino)-N,N-dimethylbut-2-enamide; 38.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-2-fluoropyridin-3-yl)-4-(dimethylamino)but-2-enamide; 39.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)-4-(piperidin-1-yl)but-2-enamide; 40.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(piperidin-1-yl)but-2-enamide; 41.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-methoxybut-2-enamide; 42.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide; 43.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 44.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide; 45.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(3-fluoropyrrolidin-1-yl)but-2-enamide; 46.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide;47. (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide(Isomer-1 of compound-46); 48.E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide(Isomer-2 of compound-46); 49.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((R)-3-fluoropyrrolidin-1-yl)but-2-enamide 50.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((R)-3-fluoropyrrolidin-1-yl)but-2-enamide(Isomer-1 of compound-49); 51.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((R)-3-fluoropyrrolidin-1-yl)but-2-enamide(Isomer-2 of compound-49); 52.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide; 53.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide (Isomer-1 ofcompound-52); 54.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide (Isomer-2 ofcompound-52); 55.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(diethylamino)but-2-enamide; 56.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide; 57.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(3-fluoropiperidin-1-yl)but-2-enamide; 58.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-2-fluoropyridin-3-yl)-4-morpholinobut-2-enamide; 59.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-6-fluoropyridin-2-yl)-4-morpholinobut-2-enamide; 60.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)-4-morpholinobut-2-enamide; 61.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-3-yl)-4-morpholinobut-2-enamide; 62.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(methoxy(methyl)amino)but-2-enamide; 63.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-3-fluoropyridin-2-yl)-4-morpholinobut-2-enamide; 64.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-2-fluoropyridin-3-yl)-4-(3-fluoropyrrolidin-1-yl)but-2-enamide; 65.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-methoxy- [1,1′-biphenyl]-4-yl)acrylamide;66.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-methyl-[1,1′-biphenyl]-4-yl)acrylamide; 67.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3,5-dimethyl-[1,1′-biphenyl]-4-yl)acrylamide; 68.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-enamide;69. (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(1H-imidazol-1-yl)but-2-enamide; 70.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)but-2-enamide; 71.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)but-2-enamide(Isomer-1 of compound-70); 72.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)but-2-enamide(Isomer-2 of compound-70); 73.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2-methoxy-[1,1′-biphenyl]-4-yl)acrylamide; 74.N-((5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)methyl)acrylamide; 75.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)acrylamide; 76.2-(3-(1-acryloylindolin-5-yl)phenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide; 77.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((2S,4S)-4-fluoro-2-(methoxymethyl)pyrrolidin-1-yl)but-2-enamide; 78.(E)-4-(3-cyanopyrrolidin-1-yl)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 79.N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)acrylamide; 80.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide; 81.methyl((E)-4-((5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)amino)-4-oxobut-2-en-1-yl)-L-prolinate; 82.(E)-4-((S)-2-(cyanomethyl)pyrrolidin-1-yl)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 83.4-acrylamido-N-(3-((5-ethyl-1H-pyrazol-3-yl)amino)phenyl)benzamide; 84.(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanamide; 85.(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)phenyl)propanamide; 86.N-(3′-(2-((5-methyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)-[1,1′-biphenyl]-4-yl)acrylamide; 87.N-(3′-(1-((5-ethyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide; 88.N-(3′-(1-((5-(tert-butyl)-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide; 89.(E)-N-(3-((1H-indazol-3-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide; 90.N-(3′-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide; 91.(E)-N-(3′-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 92.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide; 93.(S,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide; 94.(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1-(3-(6-(4-(pyrrolidin-1-yl)but-2-enamido)pyridin-3-yl)phenyl)cyclopropane-1-carboxamide; and 95.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-methyl-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In certain embodiments, the present invention provides a compoundselected from the group consisting of:

Compound No. IUPAC name 96.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide; 97.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(3-fluoropyrrolidin-1-yl)but-2-enamide; 98.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(3-hydroxypyrrolidin-1-yl)but-2-enamide; 99.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(piperidin-1-yl)but-2-enamide; 100.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(3-fluoropiperidin-1-yl)but-2-enamide; 101.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(3-hydroxypiperidin-1-yl)but-2-enamide; 102.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(4-fluoropiperidin-1-yl)but-2-enamide; 103.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(4-hydroxy-4-methylpiperidin-1-yl)but-2-enamide;104.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(4,4-difluoropiperidin-1-yl)but-2-enamide;105.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(diethylamino)but-2-enamide; 106.(E)-N-(1-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)piperidin-4-yl)-4-(dimethylamino)but-2-enamide; 107.(E)-N-(3-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-1-methyl-1H-pyrazol-5-yl)-4-(dimethylamino)but-2-enamide; 108.(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)phenyl)propanamide; 109.3-(1((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl(E)-4-(4- (dimethylamino)but-2-enoyl)piperazine-1-carboxylate; 110.(E)-4-((S)-2-cyanopyrrolidin-1-yl)-N-(5-(3-((S)-1-((5-cyclopropyl-1H-pyrazol-3 -yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 111.(E)-4-((2S,4S)-2-(cyanomethyl)-4-fluoropyrrolidin-1-yl)-N-(5-(3-((S)-1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 112.(E)-N-(3′-((S)-1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3 -fluoro-[1,1′-biphenyl]-4-yl)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)but-2-enamide; 113.(E)-N-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-4-(4-(dimethylamino)but-2-enoyl)morpholine-2-carboxamide; 114.(E)-N-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-4-(4-(dimethylamino)but-2-enamido)tetrahydro-2H-pyran-3-carboxamide ; 115.(E)-N-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-1-(4-(dimethylamino)but-2-enoyl)pyrrolidine-2-carboxamide; 116.(E)-N-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-1-(4-(dimethylamino)but-2-enoyl)piperidine-2-carboxamide; 117.(E)-N-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-1-(4-(dimethylamino)but-2-enoyl)piperidine-3-carboxamide; 118.(E)-N-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-4-(dimethylamino)but-2-enamide; 119.(E)-N-(4-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-4-(dimethylamino)but-2-enamide; 120.(E)-N-(2-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-4-(dimethylamino)but-2-enamide; 121.2-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl(E)-4-(4- (dimethylamino)but-2-enoyl)piperazine-1-carboxylate; 122.4-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl(E)-4-(4- (dimethylamino)but-2-enoyl)piperazine-1-carboxylate; 123.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-6-fluoropyridin-2-yl)-4-(dimethylamino)but-2-enamide; 124.(E)-N-(3-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-4-yl)-4-morpholinobut-2-enamide; 125.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-2-yl)-4-morpholinobut-2-enamide; 126.(E)-N-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-4-(4-(dimethylamino)but-2-enoyl)piperazine-1-carboxamide; 127.(E)-N-(6-(3-((S)-1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide;128.(E)-N-(6-(3-((S)-1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide;129.(E)-N-(5-(3-((S)-1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-3-(trifluoromethyl)pyrrolidin-1-yl)but-2-enamide;130.(E)-4-((2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl)-N-(5-(3-((S)-1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide;131.(E)-4-((S)-2-cyanopyrrolidin-1-yl)-N-(5-(3-((S)-1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 132.(S,E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(diethylamino)but-2-enamide; 133.(E)-N-(4-(3-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-4-methylisoquinolin-6-yl)phenyl)-4-(dimethylamino)but-2-enamide; 134.(E)-N-(4-(4-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)pyridin-2-yl)phenyl)-4-(dimethylamino)but-2-enamide; 135.(E)-N-(4-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)cyclohexyl)-4-(dimethylamino)but-2-enamide; 136.(E)-N-(3-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)cyclohexyl)-4-(dimethylamino)but-2-enamide; 137.(E)-4-(dimethylamino)-N-(3′-(1-oxo-1-(pyrazolo[1,5-a]pyridin-2-ylamino)propan-2-yl)-[1,1′-biphenyl]-4-yl)but-2-enamide; 138.(E)-N-(3′-(3-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1,1,1-trifluoro-3-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 139.(E)-N-(3′-(1-((5-cyclopentyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 140.(E)-N-(3′-(1-((5-cyclohexyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 141.(E)-N-(3′-(1-((5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 142.(E)-N-(3′-(1-((5-cyclopropyl-4-(pyridin-2-yl)-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; and 143.(E)-N-(3′-(3-(5-cyclopropyl-1H-pyrazol-3-yl)-1-methylureido)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In certain embodiments, when R₁ is hydrogen, the compounds of thepresent invention are known to rapidly equilibrate, in solution, asadmixtures of both tautomers:

Accordingly, in the present invention, where only one tautomer isindicated for the compounds of formula (I), is also within the scope ofthe present invention, unless specifically noted otherwise.

In certain embodiments, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof or a stereoisomer thereof as described hereinand at least one pharmaceutically acceptable excipient (such as apharmaceutically acceptable carrier or diluent). Preferably, thepharmaceutical composition comprises a therapeutically effective amountof at least one compound described herein. The compounds described inthe present invention may be associated with a pharmaceuticallyacceptable excipient (such as a carrier or a diluent) or be diluted by acarrier or enclosed within a carrier which can be in the form of acapsule, sachet, paper or other container.

In yet another embodiment, the compounds of the present invention arekinase inhibitors. In certain embodiments, the compounds of the presentinvention are selective CDK inhibitors (e.g., being more active ininhibiting a CDK than a non-CDK kinase). In certain embodiments, thecompounds of the present invention are selective CDK7 inhibitors (e.g.,being more active in inhibiting CDK7 than a non-CDK7 kinase).

In another embodiment, the present invention provides pharmaceuticalcomposition for use in treating and/or preventing a disease and/ordisorder associated with aberrant activity of selective transcritptionalCDKs.

In another embodiment, the present invention provides pharmaceuticalcomposition for use in treating a subject suffering from diseases and/ordisorder associated with aberrant activity of selective transcriptionalCDKs.

In another embodiment, the present invention provides a method ofinhibiting selective transcriptional CDKs in a subject, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound of the present invention.

In another embodiment, the present invention provides a method oftreating diseases and/or disorder mediated by selective transcriptionalCDKs in a subject comprising administering to the subject in needthereof a therapeutically effective amount of a compound of the presentinvention.

In an embodiment, the present invention provides pharmaceuticalcomposition comprising the compound of formula (I), for use in treatinga subject suffering from a disease or condition associated with aberrantactivity of selective transcriptional CDKs. In another embodiment, thepresent invention provides pharmaceutical composition comprising thecompound of formula (I), for use in treating a subject suffering fromdiseases and/or disorder associated with aberrant activity oftranscriptional CDK9, CDK12, CDK13 or CDK18.

In another embodiment, the present invention provides pharmaceuticalcomposition comprising the compound of formula (I), for use in treatinga subject suffering from diseases and/or disorder associated withaberrant activity of transcriptional CDK7.

In yet another embodiment, the present invention provides a method oftreating disorders and/or diseases or condition mediated by selectivetranscriptional CDKs (CDK9, CDK12, CDK13 or CDK18) in a subjectcomprising administering a therapeutically effective amount of acompound of the present invention.

In yet another embodiment, the present invention provides a method oftreating disorders and/or diseases or condition mediated bytranscriptional CDK7 in a subject comprising administering atherapeutically effective amount of a compound of the present invention.

In yet another embodiment, the present invention provides a method ofinhibiting selective transcriptional CDKs. In another embodiment, thepresent invention provides a method of inhibiting particularlytranscriptional CDK7, CDK9, CDK12, CDK13 or CDK18; more particularlyCDK7, in a subject in need thereof by administering to the subject oneor more compounds described herein in the amount effective to causeinhibition of such receptor/kinase.

In another aspect, the present invention relates to methods ofinhibiting the activity of a kinase in a biological sample or subject.In certain embodiments, the kinase is a selective transcriptional CDK.In another embodiment, the selective transcriptional CDK is CDK9, CDK12,CDK13 or CDK18. In yet another embodiment, the selective transcriptionalCDK is particularly CDK7.

In certain embodiments, the inhibition of the activity of the kinase isirreversible. In other embodiments, the inhibition of the activity ofthe kinase is reversible.

In certain embodiments, the present invention provides compounds offormula (I) as covalent inhibitors of selective transcriptional CDKs. Inyet another embodiment, the present invention provides compounds offormula (I) as covalent inhibitors of transcriptional CDK9, CDK12, CDK13or CDK18. In yet another embodiment, the present invention providescompounds of formula (I) as covalent inhibitors of transcriptional CDK7.

The compounds of the invention are typically administered in the form ofa pharmaceutical composition. Such compositions can be prepared usingprocedures well known in the pharmaceutical art and comprise at leastone compound of the present invention. The pharmaceutical composition ofthe present invention comprises one or more compounds described hereinand one or more pharmaceutically acceptable excipients. Typically, thepharmaceutically acceptable excipients are approved by regulatoryauthorities or are generally regarded as safe for human or animal use.The pharmaceutically acceptable excipients include, but are not limitedto, carriers, diluents, glidants and lubricants, preservatives,buffering agents, chelating agents, polymers, gelling agents,viscosifying agents, solvents and the like.

The pharmaceutical composition can be administered by oral, parenteralor inhalation routes. Examples of the parenteral administration includeadministration by injection, percutaneous, transmucosal, transnasal andtranspulmonary administrations.

Examples of suitable carriers include, but are not limited to, water,salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil,gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate,sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia,stearic acid, lower alkyl ethers of cellulose, silicic acid, fattyacids, fatty acid amines, fatty acid monoglycerides and diglycerides,fatty acid esters and polyoxyethylene.

The pharmaceutical composition may also include one or morepharmaceutically acceptable auxiliary agents, wetting agents, suspendingagents, preserving agents, buffers, sweetening agents, flavouringagents, colorants or any combination of the foregoing.

The pharmaceutical compositions may be in conventional forms, forexample, tablets, capsules, solutions, suspensions, injectables orproducts for topical application. Further, the pharmaceuticalcomposition of the present invention may be formulated so as to providedesired release profile.

Administration of the compounds of the invention, in pure form or in anappropriate pharmaceutical composition, can be carried out using any ofthe accepted routes of administration of pharmaceutical compositions.The route of administration may be any route which effectivelytransports the active compound of the present invention to theappropriate or desired site of action. Suitable routes of administrationinclude, but are not limited to, oral, nasal, buccal, dermal,intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous,intraurethral, intramuscular or topical.

Solid oral formulations include, but are not limited to, tablets,capsules (soft or hard gelatin), dragees (containing the activeingredient in powder or pellet form), troches and lozenges.

Liquid formulations include, but are not limited to, syrups, emulsionsand sterile injectable liquids, such as suspensions or solutions.

Topical dosage forms of the compounds include ointments, pastes, creams,lotions, powders, solutions, eye or ear drops, impregnated dressings andmay contain appropriate conventional additives such as preservatives,solvents to assist drug penetration.

The pharmaceutical compositions of the present invention may be preparedby conventional techniques known in literature.

Suitable doses of the compounds for use in treating the diseases ordisorders described herein can be determined by those skilled in therelevant art. Therapeutic doses are generally identified through a doseranging study in humans based on preliminary evidence derived from theanimal studies. Doses must be sufficient to result in a desiredtherapeutic benefit without causing unwanted side effects. Mode ofadministration, dosage forms and suitable pharmaceutical excipients canalso be well used and adjusted by those skilled in the art. All changesand modifications are envisioned within the scope of the presentinvention.

In one embodiment, the compounds as disclosed in the present inventionare formulated for pharmaceutical administration.

Yet another embodiment of the present invention provides use of thecompounds as disclosed in the present invention in the treatment andprevention of diseases and/or disorder associated with the aberrantactivity of selective transcriptional CDKs, particularly the selectivetranscriptional CDK is CDK7, CDK9, CDK12, CDK13 or CDK18; moreparticularly CDK7.

Yet another embodiment of the present invention provides use of thecompound or a pharmaceutically acceptable salt thereof, in treatingand/or preventing a disease for which the symptoms thereof are treated,improved, diminished and/or prevented by inhibition of selectivetranscriptional CDKs, particularly the selective transcriptional CDK isCDK7, CDK9, CDK12, CDK13 or CDK18; more particularly CDK7.

According to yet another embodiment, the selective transcriptional CDKmediated disorder and/or disease or condition is proliferative diseaseor disorder or condition.

In yet another embodiment, the diseases and/or disorder mediated byselective transcriptional CDKs is selected from, but not limited to thegroup consisting of a cancer, an inflammatory disorder, anauto-inflammatory disorder or an infectious disease.

In other embodiments, the proliferative disease to be treated orprevented using the compounds of formula (I) will typically beassociated with aberrant activity of CDKs, more particularly with CDK7,CDK9, CDK12, CDK13 or 18. Aberrant activity of CDK7, CDK9, CDK12, CDK13or CDK18 may be an elevated and/or an inappropriate (e.g., abnormal)activity of CDK7, CDK9, CDK12, CDK13 or CDK18. In certain embodiments,CDK7, CDK9, CDK12, CDK13 or CDK18 are not overexpressed, and theactivity of CDK7, CDK9, CDK12, CDK13 or CDK18 are elevated and/orinappropriate. In certain other embodiments, CDK7, CDK9, CDK12, CDK13 orCDK18 are overexpressed, and the activity of CDK7, CDK9, CDK12, CDK13 orCDK18 are elevated and/or inappropriate. The compounds of formula (I),and pharmaceutically acceptable salts or stereoisomers, and compositionsthereof, inhibit the activity of CDK7, CDK9, CDK12, CDK13 or CDK18 andhave been useful in treating and/or preventing proliferative diseases.

According to yet another embodiment, the compounds of the presentinvention are expected to be useful in the therapy of proliferativediseases such as viral diseases, fungal diseases,neurological/neurodegenerative disorders, autoimmune, inflammation,arthritis, anti-proliferative (e.g., ocular retinopathy), neuronal,alopecia and cardiovascular diseases.

According to yet another embodiment, the compounds of the presentinvention are useful in the treatment of a variety of cancers, includingbut not limited to carcinoma, including that of the breast, liver, lung,colon, kidney, bladder, including small cell lung cancer, non-small celllung cancer, head and neck, thyroid, esophagus, stomach, pancreas,ovary, gall bladder, cervix, prostate and skin, including squamous cellcarcinoma; hematopoietic tumors of lymphoid lineage, including leukemia,acute lymphoblastic leukemia, acute lymphocytic leukemia, Hodgkinslymphoma, non-Hodgkins lymphoma, B-cell lymphoma, T-cell lymphoma, hairycell lymphoma, myeloma, mantle cell lymphoma and Burkett's lymphoma;hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia; tumors of masenchymal origin, including fibrosarcoma andrhabdomyosarcoma; tumors of the central and peripheral nervous system,including astrocytoma, neuroblastoma, glioma and schwannomas; and othertumors, including seminoma, melanoma, osteosarcoma, teratocarcinoma,keratoctanthoma, xenoderoma pigmentosum, thyroid follicular cancer andKaposi's sarcoma.

According to yet another embodiment, the subject is a mammal includinghuman.

According to yet another embodiment, the present invention providescompounds or pharmaceutically acceptable salts or stereoisomers thereof,for use as a medicament.

According to yet another embodiment, the invention provides the use ofthe compounds of the present invention in the manufacture of amedicament.

According to yet another embodiment, the present invention providescompounds or pharmaceutically acceptable salts or stereoisomers thereof,for use in the treatment of cancer.

According to yet another embodiment, the invention provides the use ofthe compounds of the present invention in the manufacture of amedicament for the treatment of diseases and/or disorder associated withthe aberrant activity of selective transcriptional CDKs.

In yet another embodiment, the invention provides the use of thecompounds of the present invention in the manufacture of a medicamentfor the treatment of cancer.

According to yet another embodiment, the present invention providescompounds for use as a medicament for treating a subject suffering fromdiseases and/or disorder associated with aberrant activity of selectivetranscriptional CDKs.

According to yet another embodiment, the present invention comprisesadministering to the subject in need thereof a therapeutically effectiveamount of a compound of the present invention along with one or moreadditional chemotherapeutic agents independently selected fromanti-proliferative agents, anti-cancer agents, immunosuppressant agentsand pain-relieving agents.

The method(s) of treatment of the present invention comprisesadministering a safe and effective amount of a compound according toformula (I) or a pharmaceutically acceptable salt thereof to a patient(particularly a human) in need thereof.

Compounds of the invention are indicated both in the therapeutic and/orprophylactic treatment of the above-mentioned conditions. For theabove-mentioned therapeutic uses the dosage administered will, ofcourse, vary with the compound employed, the mode of administration, thetreatment desired and the disorder or disease indicated.

The compounds of the present invention may be used as single drug or asa pharmaceutical composition in which the compound is mixed with variouspharmacologically acceptable materials.

According to one embodiment, the compounds of the present invention canalso contain unnatural proportions of atomic isotopes at one or more ofthe atoms that constitute such compounds. For example, the presentinvention also embraces isotopically-labeled variants of the presentinvention which are identical to those recited herein, but for the factthat one or more atoms of the compound are replaced by an atom havingthe atomic mass or mass number different from the predominant atomicmass or mass number usually found in nature for the atom. All isotopesof any particular atom or element as specified are contemplated withinthe scope of the compounds of the invention and their uses. Exemplaryisotopes that can be incorporated in to compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, chlorine and iodine, such as ²H (“D”), ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I.Isotopically labeled compounds of the present invention can generally beprepared by following procedures analogous to those disclosed in theschemes and/or in the examples herein below, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.

The following abbreviations refer respectively to the definitionsherein: LDA (Lithium diisopropylamide); K₂CO₃ (Potassium carbonate);KOAc (Potassium acetate); EtOH (Ethanol); NH₃ solution (Ammoniasolution); Prep TLC (Preparative Thin layer Chromatography); rt(Retention time); RT (Room temperature); DMF (Dimethylformamide); h(hour); NaOH (Sodium hydroxide); HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid-hexafluorophosphate); LC-MS (Liquid chromatography massspectroscopy); HCl (Hydrochloric acid); THE (tetrahydrofuran); DCM(Dichloromethane); TFA (Trifluoroacetic acid); TLC (Thin layerchromatography); DIPEA (Diisopropyl Ethyl amine); Na₂SO₄ (Sodiumsulphate); ACN/CH₃CN (Acetonitrile); PdCl₂(dppf)-DCM(1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethanecomplex); Bpin₂ (Bis(pinacolato)diboron); DMSO-d₆ (Dimethylsulfoxide-d); Boc₂O (Ditert-butyl dicarbonate); HPLC (High pressureliquid chromatography); NaHCO₃ (Sodium bicarbonate); Pd₂(dba)₃(Tris(dibenzylideneacetone)dipalladium(0)); TEA (triethyl amine), Cs₂CO₃(Cesium carbonate); MHz (mega hertz); s (singlet); m (multiplet); and d(doublet).

General Modes of Preparation:

Following general guidelines apply to all experimental proceduresdescribed here. Until otherwise stated, experiments are performed underpositive pressure of nitrogen, temperature described are the externaltemperature (i.e. oil bath temperature). Reagents and solvents receivedfrom vendors are used as such without any further drying orpurification. Molarities mentioned here for reagents in solutions areapproximate as it was not verified by a prior titration with a standard.All reactions are stirred under magnetic stir bar. Cooling to minustemperature was done by acetone/dry ice or wet ice/salts. Magnesiumsulfate and sodium sulfate were used as solvent drying agent afterreaction work up and are interchangeable. Removing of solvents underreduced pressure or under vacuum means distilling of solvents in rotaryevaporator.

Compounds of this invention may be made by synthetic chemical processes,examples of which are shown herein. It is meant to be understood thatthe order of the steps in the processes may be varied, that reagents,solvents and reaction conditions may be substituted for thosespecifically mentioned and that vulnerable moieties may be protected anddeprotected, as necessary.

The specifics of the process for preparing compounds of the presentinvention are detailed in the experimental section.

The present invention shall be illustrated by means of some examples,which are not construed to be viewed as limiting the scope of theinvention.

EXPERIMENTAL

Unless otherwise stated, work-up includes distribution of the reactionmixture between the organic and aqueous phases, separation of layers anddrying the organic layer over anhydrous sodium sulphate, filtration andevaporation of the solvent. Purification, unless otherwise mentioned,includes purification by silica gel chromatographic techniques,generally using ethyl acetate/petroleum ether mixture of a suitablepolarity as the mobile phase.

Analysis for the compounds of the present invention unless mentioned,was conducted in general methods well known to a person skilled in theart. Having described the invention with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification. The invention isfurther defined by reference to the following examples, describing indetail the analysis of the compounds of the invention.

It will be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe scope of the invention. Some of the intermediates were taken to nextstep based on TLC results, without further characterization, unlessotherwise specified.

Synthesis of Intermediates Scheme-1: Synthesis of2-(3-bromophenyl)propanoic Acid

2-(3-bromophenyl)acetic acid (3 g, 13.95 mmol) in THF (15 mL) was addedto a solution of 2M LDA (22 mL, 41.8 mmol) at −78° C. over a period of10 min. The reaction mass was stirred for 1 h at −78° C. followed by thedrop wise addition of methyl iodide (6.3 g, 44.6 mmol) over a period of10 min. The reaction mass was stirred at room temperature for overnight.The reaction mass was quenched with 2N HCl and concentrated underreduced pressure to remove excess amount of THF. The residue was dilutedwith ether, washed twice with 2N HCl, extracted the ether layer with 10%NaOH. The combined NaOH layer was acidified with 6N HCl, extracted thecompound to ether. The ether layer was washed with water followed bybrine, dried and concentrated under reduced pressure to afford the crudecompound (2.5 g, 78%). LCMS: m/z=229.1 (M+H)⁺.

Scheme-2: Synthesis of 5-cyclopropyl-1-methyl-1H-pyrazol-3-amine

Methyl hydrazine (1 mL) was added to a solution of3-cyclopropyl-3-oxopropanenitrile (1 g, 9.17 mmol) in ethanol (15 mL).The resulting reaction mass was heated to reflux for 12 h. The reactionmass was quenched with ice cold water and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous sodiumsulphate and concentrated under reduced pressure to afford the titlecompound (1.1 g, 97%) LCMS: m/z=138 (M+H)⁺.

Scheme-3: Synthesis of(E)-N-(5-bromopyridin-2-yl)-4-morpholinobut-2-enamide

Step-i: (E)-4-bromobut-2-enoic acid (4.5 g, 27.7 mmol) was taken in DCM(30 mL) with catalytic amount of DMF followed by the addition of oxalylchloride (5 mL). The reaction mass was allowed to stir for 1.5 h at RT,evaporated the solvent under vacuum. The residue was dissolved in DCMand was added to the pre cooled solution of 5-bromopyridin-2-amine (3.0g, 17.34 mmol) in acetonitrile (50 mL) and DIPEA (11.0 mL, 69.36 mmol)at 0° C. The resulting reaction mixture was stirred for 2 h, added waterand extracted with DCM. The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The crude was purified by silica gel column chromatography byeluting with 10% methanol in DCM to afford(E)-4-bromo-N-(5-bromopyridin-2-yl)but-2-enamide (1.25 g, 40%), LCMS:m/z=320.9 (M+H)⁺.

Step-ii: To a stirred solution of(E)-4-bromo-N-(5-bromopyridin-2-yl)but-2-enamide (1.0 g, 3.13 mmol) inacetonitrile (20 mL) was added potassium carbonate (1.0 g, 7.83 mmol)and morpholine (0.39 g, 4.7 mmol) at room temperature. The reactionmixture was heated to 60° C. for about 2 h, concentrated the reactionmixture under vacuum. The crude was purified by neutral alumina columnchromatography using 10% methanol in DCM to afford the title compound(0.8 g, 60%), LCMS: m/z=326.1 (M+H)⁺.

Scheme-4: Synthesis of 4-acrylamidobenzoic Acid

A solution of 4-aminobenzoic acid (1.40 g, 10 mmol) in DMF (10 mL) andpyridine (0.5 ml) was cooled to 0° C. To this solution was addedacryloyl chloride (0.94 g, 10 mmol) and the resulting mixture wasstirred for 3 hours at RT. The mixture was poured into 200 ml of waterand the white solid obtained was filtered, washed with water and ether,dried to afford the title compound which was used in the next stepwithout purification (1.8 g) LCMS: m/z=192.1 (M+H)⁺.

Scheme-5: Synthesis of N-(5-bromopyridin-2-yl)acrylamide

To a solution of 5-bromopyridin-2-amine (0.5 g, 2.92 mmol) in ACN (20mL) was added water (2 mL), DIPEA (0.75 g, 5.84 mmol) and acryloylchloride (0.26 g, 2.92 mmol) at 0° C. After 30 min, the reaction mixturewas quenched with ice-water and diluted with EtoAc. The aqueous layerwas separated and extracted with EtOAc (2×25 mL). The combined organicphase was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude residue was purified by silica gel column byeluting with 10%-30% ethyl acetate-hexane system to afford the titlecompound (0.3 g, 48%) LCMS: m/z=227.8 (M+H)⁺.

Scheme-6: Synthesis of 1-(5-bromoindolin-1-yl)prop-2-en-1-one

To a solution of 5-bromoindoline (0.5 g, 2.51 mmol) in DCM (5 mL) wasadded TEA (0.63 mL, 5.02 mmol) and acryloyl chloride (0.23 g, 2.51 mmol)at 0° C. After 30 min, the reaction mixture was quenched with ice-waterand diluted with EtOAc. The aqueous layer was separated and extractedwith EtOAc (2×25 mL). The combined organic phase was washed with brine,dried over Na₂SO₄, filtered and concentrated. The crude residue waspurified by silica gel column by eluting with 10%-30% ethylacetate-hexane system to afford the title compound (0.4 g, 63%) LCMS:m/z=253.8 (M+H)⁺.

Scheme-7: Synthesis of N-((5-bromopyridin-2-yl)methyl)acrylamide

To a solution of (5-bromopyridin-2-yl)methanamine (0.5 g, 2.7 mmol) inACN (20 mL) was added water (2 mL), DIPEA (0.94 mL, 5.4 mmol) andacryloyl chloride (0.24 g, 2.7 mmol) at 0° C. After 30 min, the reactionmixture was quenched with ice-water and diluted with EtoAc. The aqueouslayer was separated and extracted with EtOAc (2×25 mL). The combinedorganic phase was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude residue was purified by silica gel columnchromatography by eluting with 0-5% MeOH-DCM to afford the titlecompound (0.3 g, 46%) LCMS: m/z=240.9 (M+H)⁺.

Examples General Synthetic Scheme Scheme-8:

wherein, ring A, ring B, R₁, R₂, R₃, R₄, L₁ and m are as defined informula (I);

Some compounds of the present invention may be generally synthesizedutilizing the process outlined in Scheme-8. The commercially availableor synthesized intermediate-b was converted to corresponding acidchloride in presence of suitable reagents and solvents (DCM, catalyticDMF, oxalyl chloride, RT, 1.5 h) which upon reacting with intermediate-ain presence of suitable reagents and solvents (pyridine, 0° C.-RT, 12 h;or DCM, TEA, 0° C.-RT, 12 h) afforded intermediate-c. Treatment ofintermediate-c with intermediate-d (boronic acid or boronate ester) bySuzuki coupling conditions in presence of suitable catalyst such asPd(dppf)Cl₂.DCM or PdCl₂(PPh₃)₂, suitable base such as potassiumcarbonate or cesiumcarbonate and in the presence of suitable solvent(s)such as 1,4-dioxane and/or water gave intermediate-e. Thisintermediate-e upon reaction with corresponding acid chloride ofintermediate-f for 1 hour at room temperature followed by reaction with2M N,N-dimethylamine in THE in presence of DIPEA and suitable solventsuch as ACN afforded the product of interest.

The present invention is further exemplified, but not limited, by thefollowing examples that illustrate the preparation of compoundsaccording to the invention.

Example-1: Synthesis of(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide(Compound-1)

Step-i: Synthesis of tert-butyl3-(2-(3-bromophenyl)propanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate

2-(3-bromophenyl)propanoic acid (1 g, 4.36 mmol) was taken in DCM at 0°C. with catalytic amount of DMF and added oxalyl chloride (1.1 g, 8.7mmol). The reaction mass was stirred at room temperature for 1.5 h. Thereaction mass was concentrated under reduced pressure. Re-dissolved theresidue in DCM and added to the cooled solution of tert-butyl3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate (0.876 g, 3.93 mmol)(synthesis carried out as described in reference Tetrahedron Letters,2005, vol. 46, #6p. 933-935) in pyridine (20 mL) at 0° C. The resultantreaction mass was stirred at room temperature for 12 h. The reactionmass was concentrated under reduced pressure and the residue wasdissolved in DCM, washed with saturated NaHCO₃ solution and brine. Theorganic layer was dried over anhydrous sodium sulphate and concentratedunder reduced pressure and the crude was purified by silica gel columnchromatography by eluting with 15% ethyl acetate-hexane to afford thetitle compound (0.5 g, 26.45%) LCMS: m/z=336.1 (M-Boc+3).

Step-ii: Synthesis of2-(4′-amino-[1,1′-biphenyl]-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide

To a degassed solution of tert-butyl3-(2-(3-bromophenyl)propanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate(0.5 g, 1.15 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.378 g, 1.72mmol) in 1,4-dioxane (20 mL) and water (4 mL), added Cs₂CO₃ (1.12 g,3.44 mmol). The reaction mass was stirred for 10 minutes and degassedfurther for 10 min and added PdCl₂(dppf).DCM (0.046 g, 0.057 mmol). Thereaction mass was heated for 12 h at 110° C. in a sealed tube. Thereaction mass was cooled to room temperature and diluted with water andethyl acetate. The separated organic layer was dried over anhydroussodium sulphate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography by eluting with 15% ethylacetate-hexane to afford the title compound (0.2 g, 50%) LCMS: m/z=347.2(M+H)⁺.

Step-iii: Synthesis of(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide

(E)-4-bromobut-2-enoic acid (0.14 g, 0.86 mmol) was taken in DCM (5 mL)with catalytic amount of DMF followed by the addition of oxalyl chloride(0.121 g, 0.95 mmol). Stirred the reaction mass for 1.5 h, evaporatedthe reaction mass under reduced pressure to residue. Re dissolved thereaction mass in DCM (2 mL) and was added at 0° C. to a mixture of2-(4′-amino-[1,1′-biphenyl]-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide(0.15 g, 0.43 mmol) in acetonitrile (10 mL) and DIPEA (0.4 mL, 2.16mmol). The resulting reaction mixture was stirred for 10 minutes at 0°C. and after completion of the reaction, a solution of N,N-dimethylamine (2M in THF, 1 mL, 2.16 mmol) was added and then allowedto stir at room temperature for 12 h. The reaction mixture was quenchedwith saturated NaHCO₃ solution and diluted with DCM. The aqueous layerwas separated and extracted with DCM (2×25 mL). The combined organicphase was washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure and purified the residue with silicagel column chromatography by eluting with 10% methanol-DCM to afford thetitle compound (0.015 g, 7.57%). ¹HNMR (DMSO-d₆, 400 MHz): δ 12.0 (s,1H), 10.28 (d, 2H), 7.77 (d, 2H), 7.62 (t, 3H), 7.49 (s, 1H), 7.30-7.39(m, 2H), 6.74-6.81 (m, 1H), 6.41 (d, 1H), 6.13 (s, 1H), 3.89 (dd, 1H),3.56-3.58 (m, 2H), 2.70 (s, 6H), 1.77-1.84 (m, 1H), 1.41 (d, 2H),1.25-1.28 (m, 1H), 0.87 (d, 2H), 0.60 (d, 2H); LCMS: m/z=458.3 (M+H)⁺;HPLC: 98.15%, rt: 6.54 min.

Racemic(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide(0.1 g, Compound-1) was separated by using chiral prep HPLC column.(Method: Column: Lux 5 μCellulose-4 (10.0×250 mm), Elution: isocratic(95:5), A=ACN, B=0.1% DEA in EtOH) to afford the pure Isomer-1 (0.04 g)and Isomer-2 (0.04 g).

Isomer-1 (Compound-2): ¹HNMR (DMSO-d₆, 400 MHz): δ 12.0 (brs, 1H), 10.42(s, 1H), 10.17 (s, 1H), 7.75 (d, 2H), 7.58-7.64 (m, 3H), 7.48 (d, 1H),7.36 (t, 1H), 7.30 (d, 1H), 6.72-6.76 (m, 1H), 6.28 (d, 1H), 6.12 (s,1H), 3.87-3.89 (m, 1H), 3.05 (d, 2H), 2.17 (s, 6H), 1.80 (brs, 1H), 1.40(d, 3H), 0.87 (dd, 2H), 0.60 (d, 2H). LCMS: m/z=458.35 (M+H)⁺; HPLC:97.98%, rt: 6.06 min.; Chiral HPLC: 97.67%, rt: 6.88 min.

Isomer-2 (Compound-3): ¹HNMR (DMSO-d₆, 400 MHz): δ 12.0 (brs, 1H), 10.42(s, 1H), 10.17 (s, 1H), 7.75 (d, 2H), 7.58-7.64 (m, 3H), 7.48 (d, 1H),7.36 (t, 1H), 7.30 (d, 1H), 6.72-6.76 (m, 1H), 6.28 (d, 1H), 6.12 (s,1H), 3.87-3.89 (m, 1H), 3.05 (d, 2H), 2.17 (s, 6H), 1.80 (brs, 1H), 1.40(d, 3H), 0.87 (dd, 2H), 0.60 (d, 2H). LCMS: m/z=458.35 (M+H)⁺; HPLC:96.64%, rt: 6.05 min; Chiral HPLC: 98.74%, rt: 10.16 min.

The compounds listed in the below table-1 were prepared by proceduresimilar to the one described in Example-1 with appropriate variations inreactants, quantities of reagents, protections and deprotections,solvents and reaction conditions. The characterization data of thecompounds are also summarized herein the table-1.

TABLE 1 Comp.No. Structure Characterization data 4

¹HNMR (DMSO-d₆, 400 MHz): δ 10.46 (d, 2H), 9.75 (s, 1H), 7.78 (d, 2H),7.48-7.52 (m, 3H), 7.32-7.35 (m, 1H), 7.21-7.26 (m, 1H), 6.74-6.78 (m,1H), 6.47 (d, 1H), 6.11 (s, 1H), 3.96 (t, 2H), 3.85-3.90 (m, 1H), 2.81(d, 6H), 1.79-1.82 (m, 1H), 1.39 (d, 3H), 0.86 (dd, 2H), 0.60 (dd, 2H);LCMS: m/z = 476.1 (M + H)⁺; HPLC: 93.72%, rt: 6.20 min. 5

¹HNMR (DMSO-d₆, 400 MHz): δ 10.46 (d, 2H), 9.75 (s, 1H), 7.76 (d, 2H),7.65 (d, 1H), 7.58 (dd, 2H), 7.52-7.60 (m, 1H), 7.22 (t, 1H), 6.71-6.78(m, 1H), 6.46 (d, 1H), 6.12 (s, 1H), 4.14 (d, 1H), 3.34-3.39 (d, 2H),2.81 (s, 6H), 1.46-1.83 (m, 1H), 1.45 (d, 3H), 0.85-0.88 (m, 2H),0.59-0.63 (m, 2H); LCMS: m/z = 476.1 (M + H)⁺; HPLC: 94.10%, rt: 10.18min. 6

¹HNMR (DMSO-d₆, 400 MHz): δ 10.14 (s, 1H), 9.92 (s, 1H), 7.72 (d, 2H),7.56-7.60 (m, 3H), 7.49 (d, 1H), 7.37 (t, 1H), 7.28 (d, 1H), 6.68- 6.74(m, 1H), 6.24 (d, 1H), 5.81 (s, 1H), 3.88- 3.93 (m, 1H), 3.41 (s, 3H),3.03 (d, 2H), 2.14 (s, 6H), 1.67-1.73 (m, 1H), 1.41 (d, 3H), 0.71- 0.76(m, 2H), 0.49-0.53 (m, 2H); LCMS: m/z = 472.2 (M + H)⁺; HPLC: 97.67%,rt: 6.72 min. 7

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.56 (s, 1H), 10.18 (s, 1H),7.75 (d, 2H), 7.59 (d, 2H), 7.50 (d, 1H), 7.36 (t, 1H), 7.25 (d, 1H),6.72-6.76 (m, 1H), 6.26-6.30 (m, 1H), 6.10 (s, 1H), 3.62 (s, 2H),3.33-3.38 (m, 1H), 3.05 (d, 2H), 2.17 (s, 6H), 1.78-1.81 (m, 1H), 0.86(dd, 2H), 0.61 (d, 2H); LCMS: m/z = 444.0 (M + H)⁺; HPLC: 95.97%, rt:5.90 min. 8

¹HNMR (DMSO-d₆, 400 MHz): δ 12.0 (s, 1H), 10.42 (s, 1H), 10.21 (s, 1H),7.74 (d, 2H), 7.64 (s, 1H), 7.59 (d, 2H), 7.49 (d, 1H), 7.37 (t, 1H),7.31 (d, 1H), 6.71-6.77 (m, 1H), 6.24-6.49 (m, 2H), 3.84-3.89 (m, 2H),3.76-3.78 (m, 1H), 3.07 (d, 2H), 2.18 (s, 6H), 1.41 (d, 3H), 1.12 (t,3H). LCMS: m/z = 446 35 (M + H)⁺; HPLC: 93.28%, rt: 5.99 min. 9

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.46 (s, 1H), 10.18 (s, 1H),7.77 (d, 2H), 7.66 (s, 1H), 7.60 (d, 2H), 7.51 (d, 1H), 7.40 (t, 1H),7.31 (d, 1H), 6.77-6.72 (m, 1H), 6.29 (d, 2H), 3.90 (d, 1H), 3.08 (d,2H), 2 49 (s, 6H), 1.42 (d, 3H), 1.21 (s, 9H); LCMS: m/z = 474.35 (M +H)⁺; HPLC: 94.08%, rt: 3.22 min.

General Synthetic Scheme

wherein, ring A, ring B, R₁, R₂, R₃, R₄, R₅, L₁ and mare as defined informula (I); Some compounds of the present invention can be generallysynthesized utilizing the process outlined in this scheme. Thecommercially available or synthesized intermediate-b was converted tocorresponding acid chloride in presence of suitable reagents andsolvents (DCM, catalytic DMF, oxalyl chloride, RT, ˜1.5 h) which uponreacting with intermediate-a in presence of suitable reagents andsolvents (pyridine, 0° C.-RT, 12 h; or DCM, TEA, 0° C.-RT, 12 h)afforded intermediate-c. Treatment of intermediate-c with intermediate-g(4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)) undersuitable reagents and conditions (1,4-Dioxane, potassium acetate,Pd(dppf)Cl₂.DCM or PdCl₂(PPh₃)₂, 12 h, 100° C.) gave intermediate-h.Treatment of intermediate-h with intermediate-i by Suzuki couplingconditions in presence of suitable catalyst such as Pd(dppf)Cl₂.DCM orPdCl₂(PPh₃)₂, suitable base such as potassium carbonate or cesiumcarbonate and in the presence of suitable solvent(s) such as 1,4-dioxaneand/or water afforded the product of interest.

Example-2: Synthesis of(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide(Compound-10)

Step-i: Synthesis of tert-butyl5-cyclopropyl-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamido)-1H-pyrazole-1-carboxylate

To a degassed solution of tert-butyl3-(2-(3-bromophenyl)propanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate(5.0 g, 11.52 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.5 g, 13.8mmol) in 1,4-dioxane (50 mL) was added potassium acetate (3.3 g, 34.5mmol). The reaction mass was allowed to stir for 10 minutes withdegassing at RT and added PdCl₂(dppf).DCM complex (0.046 g, 0.057 mmol).The reaction mass was heated for 12 h at 100° C. in a sealed tube,cooled the reaction mass and diluted with water and ethyl acetate. Theaqueous layer was separated and re-extracted with ethyl acetate (2×25mL). The combined organic layer was dried over anhydrous sodium sulfateand concentrated under vacuum. The crude material was purified by silicagel column chromatography by eluting with 20% ethyl acetate in hexane toafford the title compound (4.0 g, 60%), LCMS: m/z=482.2 (M+H)⁺.

Step-ii: Synthesis of(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide

To a degassed solution oftert-butyl-5-cyclopropyl-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamido)-1H-pyrazole-1-carboxylate(0.5 g, 1.04 mmol) and(E)-N-(5-bromopyridin-2-yl)-4-morpholinobut-2-enamide (0.27 g, 0.83mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added Cs₂CO₃ (0.84 g,2.6 mmol). The reaction mass was allowed to stir for 10 minutes withdegassing and added PdCl₂(dppf).DCM complex (0.06 g, 0.07 mmol), heatedthe reaction mass for 12 h at 100° C. in a d sealed tube. The reactionmass was cooled and diluted with water and ethyl acetate. The aqueouslayer was separated and re-extracted with ethyl acetate (2×25 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude material was purified by silica gelcolumn chromatography by eluting with 10% methanol in DCM, furtherpurified by preparative HPLC (Method: Column: Gemini NX C18 (21.2 mm×150mm, 5 micron), Mobile phase: 0.01% NH₄OH in Water, Acetonitrile:Methanol(1:1)) to afford the title compound (0.2 g, 40%). ¹HNMR (DMSO-d₆, 400MHz): δ 12.02 (s, 1H), 10.76 (s, 1H), 10.41 (s, 1H), 8.61 (s, 1H), 8.26(d, 1H), 8.05 (d, 1H), 7.69 (s, 1H), 7.55 (d, 1H), 7.42-7.34 (m, 2H),6.82-6.75 (m, 1H), 6.47 (d, 1H), 6.12 (s, 1H), 3.91-3.86 (m, 1H),3.60-3.58 (m, 4H), 3.13 (d, 2H), 2.37 (s, 4H), 1.83-1.76 (m, 1H), 1.41(d, 3H), 0.87-0.85 (d, 2H), 0.60-0.59 (m, 2H); LCMS: m/z=501.10 (M+H)⁺;HPLC: 97.63%, rt: 4.27 min.

Racemic(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-phenyl)pyridin-2-yl)-4-morpholinobut-2-enamidewas separated by using chiral preparative HPLC column (Method: Column:Chiral Pak IA (20 mm×250 mm, 5 micron), Elution: isocratic (50:50),A=ACN, B=MeOH, Flow: 20 mL/min) to afford the pure Isomer-1 andIsomer-2.

Isomer-1 (Compound-11): ¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.77(s, 1H), 10.43 (s, 1H), 8.62-8.61 (m, 1H), 8.27 (d, 1H), 8.06 (d, 1H),7.69 (s, 1H), 7.56 (d, 1H), 7.43-7.34 (m, 2H), 6.82-6.75 (m, 1H), 6.47(d, 1H), 6.11 (s, 1H), 3.86 (m, 1H), 3.60-3.58 (m, 4H), 3.12 (d, 2H),2.38 (s, 4H), 1.83-1.76 (m, 1H), 1.41 (d, 3H), 0.89-0.84 (m, 2H),0.62-0.58 (m, 2H); LCMS: m/z=501.3 (M+H)⁺; HPLC: 99.26%, rt: 3.45 min.;Chiral HPLC: 97.58%, rt: 7.54 min.

Isomer-2 (Compound-12): ¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.75(s, 1H), 10.41 (s, 1H), 8.61-8.60 (m, 1H), 8.27-8.20 (m, 1H), 8.05 (d,1H), 7.68 (s, 1H), 7.55 (d, 1H), 7.42-7.33 (m, 2H), 6.81-6.74 (m, 1H),6.47 (d, 1H), 6.10 (s, 1H), 3.89-3.87 (m, 1H), 3.59-3.57 (m, 4H), 3.10(d, 2H), 2.31 (s, 4H), 1.81-1.77 (m, 1H), 1.40 (d, 3H), 0.87-0.85 (m,2H), 0.61-0.57 (m, 2H); LCMS: m/z=501.2 (M+H)⁺; HPLC: 99.04%, rt: 3.44min.; Chiral HPLC: 95.42%, rt: 9.07 min.

The compounds listed in the below table-2 were prepared by a proceduresimilar to the one described in Example-2 with appropriate variations inreactants, quantities of reagents, protections and deprotections,solvents and reaction conditions. The characterization data of thecompounds are also summarized herein the table-2.

TABLE 2 Comp. No. Structure Characterization Data 13

¹HNMR (DMSO-d₆, 400 MHz): δ 11.99 (s, 1H), 10.41 (s, 1H), 10.13 (m, 1H),7.73-7.71 (m, 2H), 7.60 (s, 1H), 7.60-7.54 (m, 2H), 7.46-7.44 (d, 1H),7.35-7.31 (m. 1H), 7.27-7.25 (m, 1H). 6.74-6.67 (m, 1H), 6.27-6.23 (m,1H), 6.11 (s, 1H), 3.62-3.58 (m, 1H), 3.02 (d, 2H), 2.14 (s, 6H),2.06-1.99 (m, 1H), 1.78-1.73 (m, 1H), 1.70-1.63 (m, 1H), 0.84-0.79 (m,5H), 0.58-0.57 (m, 2H); LCMS: m/z = 472.5 (M + H)⁺; HPLC: 94.51%, rt:6.18 min. 14

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.42 (s, 1H), 9.91 (s, 1H),8.09-8.05 (m, 1H), 7.65 (s, 1H), 7.65-7.51 (m, 2H), 7.44 (d, 1H),7.42-7.28 (m, 2H), 6.76-6.68 (m, 1H), 6.45 (d, 1H), 6.08 (s, 1H),3.86-3.82 (m, 1H), 3.05 (d, 2H), 2.13 (s, 6H), 1.77-1.75 (m, 1H), 1 38(d, 3H), 0.83 (m, 2H), 0.57 (m, 2H); LCMS: m/z = 476.1 (M + H)⁺; HPLC:95.68%, rt: 6.12 min. 15

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.46 (s, 1H), 10.18 (s, 1H),7.76 (d, 2H), 7.65 (s, 1H), 7.60 (d, 2H), 7.49 (d, 1H), 7.39-7.30 (m,2H), 6.78-6.71 (m, 1H), 6.32-6.27 (m, 2H), 3.93-3.88 (m, 1H), 3.07-3.05(m, 2H), 2.22-2.19 (m, 8H), 2.07-2.05 (m, 2H), 1.97-1.87 (m, 3H), 1.42(d, 3H); LCMS: m/z = 472.2 (M + H)⁺; HPLC: 98.85%, rt: 3.71 min. 16

¹HNMR (DMSO-d₆, 400 MHz): δ 12.05 (s, 1H), 10.47 (d, 2H), 8.86 (d, 1H),8.23-8.21 (m, 1H), 8.10 (s, 1H), 7.91 (d, 1H), 7,87-7.85 (m, 1H),7.40-7.39 (m, 2H), 6.81-6.77 (m, 1H), 6.32 (d, 1H), 6.14 (s, 1H),3.93-3.91 (m, 1H), 3.09-3.07 (m, 2H), 2.41 (s, 6H), 1.81-1.79 (m, 1H),1.42 (d, 3H), 0.86 (m, 2H), 0.61 (m, 2H); LCMS: m/z = 459 (M + H)⁺;HPLC: 95.54%, rt: 5.79 min. 17

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.43 (s, 1H), 10.36 (s, 1H),7.80-7.76 (d, 1H), 7.53 (s, 1H), 7 48-7.34 (m, 5H), 6.79-6.74 (m, 1H),6.29 (d, 1H), 6.13 (s, 1H), 3.91-3.86 (m, 1H), 3.05 (d, 2H), 2.18 (s,6H), 1.78 (m, 1H), 1.38 (d, 3H), 0.83-0.81 (m, 2H), 0.60-0.58 (m, 2H);LCMS: m/z = 476.2 (M + H)⁺; HPLC: 99.40%, rt: 3.44 min. 18

¹HNMR (DMSO-d₆, 400 MHz): δ 12.05 (s, 1H), 10.41 (s, 1H), 10.25 (m, 1H),7.77 (d, 2H), 7.64- 7.59 (m, 3H), 7.50 (d, 1H), 7.39-7.31 (m, 2H),6.48-6.46 (m, 1H), 6.29 (d, 1H), 6.13 (s, 1H), 5.75 (d, 1H), 3.88 (s,1H), 1.79 (m, 1H), 1.40 (d, 3H), 0.85 (d, 2H), 0.61 (d, 2H); LCMS: m/z =400.8 (M + H)⁺; HPLC: 97.91%, rt: 4.47 min 19

¹HNMR (DMSO-d₆, 400 MHz): δ 12 03 (s, 1H), 10.41 (s, 1H), 10.05 (s, 1H),8.13 (t, 1H), 7.70 (s, 1H), 7.60-7.55 (m, 2H), 7.49 (d, 1H), 7.42-7.34(m, 2H), 6.68-6.62 (m, 1H), 6.32-6.28 (m, 1H), 6.13 (s, 1H), 5.81-5.78(m, 1H), 3.92-3.87 (m, 1H), 1.84-1 78 (m, 1H), 1.42 (d, 3H), 0.88-0.86(m, 2H), 0.63-0.61 (m, 2H); LCMS: m/z = 419.1 (M + H)⁺; HPLC: 98.28%,rt: 7.07 min. 20

¹HNMR (DMSO-d₆, 400 MHz): δ 12.05 (s, 1H), 10.95 (s, 1H), 10.41 (s, 1H),8.63 (s,1H), 8.29 (d, 1H), 8.09 (d, 1H), 7.70 (s, 1H), 7.57 (d, 1H),7.44-7.35 (m, 2H), 6.67-6.54 (m, 1H), 6.35-6.30 (d, 1H), 6.13 (s, 1H),5.78 (d, 1H), 3.91-3.89 (m, 1H), 1.80-1.78 (m, 1H), 1.45 (d, 3H),0.88-0.86 (m, 2H), 0.60-0.62 (m, 2H); LCMS: m/z = 402.2 (M + H)⁺; HPLC:99.41%, rt: 3.84 min. 21

¹HNMR (DMSO-d₆, 400 MHz): δ 12.05 (s, 1H), 10.95 (s, 1H), 10.41 (s, 1H),8.63 (s, 1H), 8.29 (d, 1H), 8.09 (d, 1H), 7.70 (s, 1H), 7.57 (d, 1H),7.44-7.35 (m, 2H), 6.67- 6.54 (m, 1H), 6.35-6.30 (d, 1H), 6.13 (s, 1H),5.78 (d, 1H), 3.91-3.89 (m, 1H), 1.80-1 78 (m, 1H), 1.45 (d, 3H),0.88-0.86 (m, 2H), 0.60-0.62 (m, 2H); LCMS: m/z = 402.2 (M + H)⁺; HPLC:97.74%, rt: 6.12 min.; Chiral HPLC: 96.78 %, rt: 6.57 min. (Isomer-1 ofcompound-20) 22

¹HNMR (DMSO-d₆, 400 MHz): δ 12.05 (s, 1H), 10.95 (s, 1H), 10.41 (s, 1H),8.63 (s, 1H), 8.29 (d, 1H), 8.09 (d, 1H), 7.70 (s, 1H), 7.57 (d, 1H),7.44-7.35 (m, 2H), 6.67-6.54 (m, 1H), 6.35-6.30 (d, 1H), 6.13 (s, 1H),5.78 (d, 1H), 3.91-3.89 (m, 1H), 1.80-1.78 (m, 1H), 1.45 (d, 3H),0.88-0.86 (m, 2H), 0.60-0.62 (m, 2H); LCMS: m/z = 402.2 (M + H)⁺; HPLC:95.96%, rt: 6.11 min; Chiral HPLC: 98.55 %, rt: 12.37 min. (Isomer-2 ofcompound-20) 23

¹HNMR (DMSO-d₆, 400 MHz): δ 12.03 (s, 1H), 10.42 (s, 1H), 10.09 (s, 1H),8.15 (t, 1H), 7.55 (d, 1H), 7.47 (d, 1H), 7.37 (d, 2H), 7.28 (t, 1H),6.66-6.54 (m, 1H), 6.32-6.27 (d, 1H), 6.13 (s, 1H), 5.79 (d, 1H), 3.88(d, 1H), 1.80-1.78 (m, 1H), 1.40 (d, 3H), 0.88-0.86 (m, 2H), 0.61-0.60(m, 2H); LCMS: m/z = 436.9 (M + H)⁺; HPLC: 96.49%, rt: 4.21 min. 24

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.49-10.46 (d, 2H), 8 88 (s,1H), 8 28 (d, 1H), 8.10 (s, 1H), 7.93-7.86 (m, 2H), 7.44-7.39 (m, 2H),6.47-6.43 (m, 1H), 6.33-6.29 (d, 1H), 6.14 (s, 1H), 5.84 (d, 1H),3.95-3.89 (m, 1H), 1.81-1.78 (m, 1H), 1.42 (d, 3H), 0.88-0.86 (d, 2H),0.62-0.60 (d, 2H); LCMS: m/z = 402.2 (M + H)⁺; HPLC: 99.66%, rt: 3.54min. 25

¹HNMR (DMSO-d₆, 400 MHz): δ 12.05-11.93 (brs, 1H), 10.7 (s, 1H), 10.06(s, 1H), 8.14 (t, 1H), 7.69 (s, 1H), 7.58-7.55 (m, 2H), 7.48 (d, 1H),7.42-7.35 (m, 2H), 6.65 (dd. 1H), 6.35 (d, 1H), 6.18 (s, 1H), 5.80 (d,1H), 3.45-3.35 (m, 1H), 1.81-1.78 (m, 1H), 1.24 (s, 1H), 0.98 (d, 3H),0.86 (d, 2H), 0.67 (d, 3H), 0.61 (d, 2H); LCMS: m/z = 447.0 (M + H)⁺;HPLC: 98.63%, rt: 4.63 min. 26

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.42 (s, 2H), 8.92 (s, 1H),8.36 (s, 1H), 8.22 (s, 1H),7.44 (d, 2H), 7.37 (d, 2H), 6.51 (s, 1H),6.35-6.31 (m, 1H), 6.26 (d, 1H), 5.75 (d, 1H), 3.83-3.89 (m, 1H),2.05-1.99 (m, 1H), 1.80-1.67 (m, 2H), 0.86-0.84 (m, 5H), 0.59-0.57 (m,2H); LCMS: m/z = 416.30 (M + H)⁺; HPLC: 97.41%, rt: 7.99 min. 27

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.42 (s, 1H), 10.01 (s, 1H),8.12 (t, 1H), 7.65 (s, 1H), 7.53 (d, 2H), 7.44 (d, 1H), 7.37 (d, 2H),6.65-6.51 (m, 1H), 6.27 (d, 1H), 6.09 (s, 1H), 5.75 (d, 1H), 3.63-3.59(m, 1H), 2.05-1.99 (m, 1H), 1.83-1.69 (m, 2H), 0.86-0.84 (m, 5H),0.62-0.61 (m, 2H); LCMS: m/z = 433.3 (M + H)⁺; HPLC: 97.21%, rt: 4.33min. 28

¹HNMR (DMSO-d₆, 400 MHz): δ 11.99 (s, 1H), 10.42 (s, 1H), 9.93 (s,1H),8.10 (t, 1H), 7.69 (s, 1H), 7.59 (d, 2H), 7.45-7.35 (m, 1H), 7.35-7.33(m, 2H), 6.79-6.80 (m, 1H), 6.46 (d, 1H), 6.25 (s, 1H), 3.92-3.87 (m,1H), 3.06 (d, 2H), 2.91-2.99 (m, 1H), 2.16 (s, 6H), 1.93 (s, 2H),1.66-1.49 (m, 6H), 1.42-1.41 (m 3H); LCMS: m/z = 504.55 (M + H)⁺; HPLC:96.66%, rt: 4.66 min. 29

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.41 (s, 1H), 8.20 (d, 1H),7.64 (s, 1H), 7.51-7.43 (m, 3H), 7.37-7.35 (m, 1H), 7.37-7.27 (m, 1H),6.83-6.78 (m, 1H), 6.76 (d, 1H), 6.11 (s, 1H), 4.26-4.21 (m, 2H), 388-3.33 (m, 1H), 3.22-3.20 (m, 2H), 3.10-3.08 (m, 2H), 2.18 (s, 6H),1.83-1.77 (m, 1H), 1.37 (d, 3H), 0.84-0.82 (m, 2H), 0.62-0.57 (m, 2H);LCMS: m/z = 484.4 (M + H)⁺; HPLC: 95.47%, rt: 4.25 min. 30

¹HNMR (DMSO-d₆, 400 MHz): δ 11.85 (s, 1H), 10.3 (s, 1H), 9.64 (s, 1H),7.78-7.76 (m, 2H), 7.66-7.61 (m, 3H), 7.51 (d, 1H), 7.40-7.34 (m, 2H),6.45 (dd, 1H), 6.25 (dd, 1H), 5.77 (dd, 1H), 3.87-3.86 (brs, 1H),1.72-1.69 (m, 4H), 1.43-1.42 (m, 3H), 0.82 (d, 2H), 0.67 (d, 2H); LCMS:m/z = 415.3 (M + H)⁺; HPLC: 97.49, rt: 5.03 min. 31

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.43 (s, 1H), 9.93 (s, 1H),8.11 (t, 1H), 7.67 (s, 1H), 7.53 (d, 2H), 7.44 (d, 1H), 7.37 (d, 1H),7.17 (s, 1H), 6.79-6.75 (m, 1H), 6.49-6.45 (m, 1H), 6.18 (s, 1H),3.66-3.63 (m, 1H), 3.07-3.06 (m, 2H), 2.18 (s, 6H), 2.08-2.08 (m, 1H),1.82-1.80 (m, 1H), 1.69-1.68 (m, 1H), 0.87-0.84 (m, 5H), 0.62 (s, 2H);LCMS: m/z = 490.1 (M + H)⁺; HPLC: 98.55%, rt: 4.54 min. 32

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.40 (s, 1H), 9.91 (s, 1H),8.09 (t, 1H), 7.68 (s, 1H), 7.56-7.47 (m, 2H), 7.46 (d, 1H), 7.38-7.32(m, 2H), 6.83-6.76 (m, 1H), 6.52 (d, 1H), 6.13 (s, 1H), 3.89-3.87 (m,1H), 3.20 (d, 2H), 2.49-2.44 (m, 4H), 1.82-1.78 (m, 1H), 1.41 (d, 3H),0.99-0.96 (m, 6H), 0.86 (d, 2H), 0.62 (d, 2H); LCMS: m/z = 504.40 (M +H)⁺; HPLC: 98.75%, rt: 4.47 min. 33

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.40 (s, 1H), 9.92 (s, 1H),8.12-8.08 (m, 1H), 7.68 (s, 1H), 7.56-7.53 (m, 2H), 7.46 (d, 1H),7.40-7.32 (m, 2H), 6.83-6.77 (m, 1H), 6.46 (d, 1H), 6.11 (s, 1H), 3.91-385 (m, 1H), 3.22 (d, 2H), 2.49-2.47 (m, 4H), 1.82-1.76 (m, 1H), 1.70 (d,4H), 1.41 (d, 3H), 0.85 (d, 2H), 0.62-0.58 (m, 2H); LCMS: m/z = 502.40(M + H)⁺; HPLC: 95.31%, rt: 4.43 min. 34

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.41 (s, 1H), 9.94 (s, 1H),8.10 (t, 1H), 7.68 (s, 1H), 7.56-7.53 (m, 2H), 7.46 (d, 1H), 7.40-7.32(m, 2H), 6.78-6.72 (m, 1H), 6.48 (d, 1H), 6.11 (s, 1H), 3.91-3.85 (m,1H), 3.60 (d, 4H), 3.10 (d, 2H), 2.38 (s, 4H), 1.83-1.74 (m, 1H), 1.41(d, 3H), 0.88-0.85 (m, 2H), 0.61-0.58 (m, 2H); LCMS: m/z = 518.40 (M +H)⁺; HPLC: 98.37%, rt: 4.23 min. 35

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.41 (s, 2H), 8.85 (s, 1H),8.21 (d, 1H), 8.08 (s, 1H),7.91-7.83 (m, 2H), 7.41-7.37 (m, 2H),6.81-6.74 (m, 1H), 6.31 (d, 1H), 6.12 (s, 1H), 3.93-3.88 (m, 1H), 3.60(t, 4H), 3.16-3.13 (m, 2H), 2.39 (s, 4H), 1.83-1.76 (m, 1H), 1.40 (d,3H), 0.87-0.84 (d, 2H), 0.62-0.60 (m, 2H); LCMS: m/z = 501.40 (M + H)⁺;HPLC: 97.02%, rt: 4.17 min. 36

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.49 (s, 1H), 10.40 (s, 1H),8.87-8.86 (m, 1H), 8.23-8.20 (m, 1H), 8.10 (s, 1H), 7.90-7.84 (m, 2H),7.42-7.38 (m, 2H), 6.82-6.75 (m, 1H), 6.32-6.28 (m, 1H), 6.14 (s, 1H),3.40-3.37 (m, 1H), 3.08 (d, 2H), 2.41-2.35 (m, 1H), 2.19 (s, 6H),1.81-1.77 (m, 1H), 0.98 (d, 3H), 0.86 (d, 2H), 0.66 (m, 3H), 0.61 (s,2H); LCMS: m/z = 487.4 (M + H)⁺; HPLC: 96.73%, rt: 6.05 min. 37

¹HNMR (DMSO-d₆, 400 MHz): δ 12.00 (s, 1H), 10.42 (s, 1H), 8.07 (s, 1H),7.97 (s, 1H), 7.73 (d, 1H), 7.64 (d, 1H), 7.33-7.25 (m, 2H), 7.02-6.99(m, 1H), 6.67-6.61 (m, 2H), 6.40 (t, 1H), 6.12 (s, 1H), 3.94-3.84 (m,3H), 2.97 (s, 3H), 2.95 (s, 3H), 1.82-1.78 (m, 1H), 1.38 (d, 3H), 0.86(d, 2H), 0.61-0.59 (m, 2H); LCMS: m/z = 459.30 (M + H)⁺; HPLC: 90.11%,rt: 4.01 min. 38

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.46 (s, 1H), 10.15 (s, 1H),8.66-8.61 (m, 1H), 8.03 (s, 1H), 7.89-7.84 (m, 2H), 7.41-7.40 (m, 2H),6.82-6.75 (m, 1H), 6.53-6.47 (m, 1H), 6.12 (s, 1H), 3.92-3.90 (m, 1H),3.06-3.04 (d, 2H), 2.18 (s, 6H), 1.81 (m, 1H), 1.40 (d, 3H), 0.87-0.85(m, 2H), 0.61-0.60 (m, 2H); LCMS: m/z = 477.5 (M + H)⁺; HPLC: 97.38%,rt: 5.77 min. 39

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.44 (s, 1H), 10.37 (s, 1H),8.85-8.84 (s, 1H), 8.20 (d, 1H), 8.08 (s, 1H), 7.89 (d, 1H), 7.86-7.83(m, 1H), 7.41-7.36 (m, 2H), 6.81-6.74 (m, 1H), 6.26 (d, 1H), 6.13 (s,1H), 3.91-3.90 (m, 1H), 3.16-3.10 (m, 2H), 2.34 (s, 4H), 1.81-1.77 (m,1H), 1.54-1.51 (m, 4H), 1.41-1.39 (m, 5H), 0.85 (d, 2H), 0.62-0.59 (m,2H); LCMS: m/z = 499.60 (M + H)⁺; HPLC: 98.43% rt: 5.75 min. 40

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.74 (s, 1H), 10.40 (s, 1H),8.61 (d, 1H), 8.27 (d, 1H), 8.05 (d, 1H), 7.69 (s, 1H), 7.55 (d, 1H),7.42-7.34 (m, 2H), 6.83-6.76 (m, 1H), 6.43 (d, 1H), 6.12 (s, 1H),3.90-3.86 (m, 1H), 3.07-3.05 (d, 2H), 2.32 (s, 4H), 1.82-1.77 (m, 1H),1.53- 1.48 (m, 4H), 1.42-1.37 (m, 5H), 0.87-0.85 (d, 2H), 0.60-0.59 (m,2H); LCMS: m/z = 499.70 (M + H)⁺; HPLC: 97.36%, rt: 5.90 min. 41

¹HNMR (DMSO-d₆, 400 MHz): δ 12.00 (s, 1H), 10.81 (s, 1H), 10.43 (s, 1H),8.61 (d, 1H), 8.27 (d, 1H), 8.08-8.05 (m, 1H), 7.68 (s, 1H), 7.55 (d,1H), 7.43-7.34 (m, 2H), 6.89-6.83 (m, 1H), 6.53- 6.48 (m, 1H), 6.10 (s,1H), 4.10-4.09 (m, 2H), 3.96-3.90 (m, 1H), 3.31 (s, 3H), 1.80-1.78 (m,1H), 1.41-1.39 (d, 3H), 0.86-0.83 (m, 2H), 0.60-0.58 (m, 2H); LCMS: m/z= 446.4 (M + H)⁺; HPLC: 95.99%, rt: 4.05 min. 42

¹HNMR (DMSO-d₆, 400 MHz): δ 12.05 (s, 1H), 10.75 (s, 1H), 10.41 (d, 1H),8.61 (s, 1H), 8.28-8.26 (d, 1H), 8.07-8.05 (m, 1H), 7.69 (s, 1H), 7.55(d, 1H), 7.42-7.34 (m, 2H), 6.83-6.76 (m, 1H), 6.44 (d, 1H), 6.11 (s,1H), 3.89-3.87 (m, 1H), 3.06-3.04 (d, 2H), 2.15 (s, 6H), 1.78-1.76 (m,1H), 1.42-1.40 (d, 3H), 0.87-0.84 (m, 2H), 0.61-0.59 (m, 2H); LCMS: m/z= 459.4 (M + H)⁺; HPLC: 96.38%, rt: 4.26 min. 43

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.43 (s, 1H), 9.94 (s, 1H),8.13-8.09 (m, 1H), 7.67 (s, 1H), 7.55-7.52 (m, 2H), 7.46-7.44 (m, 1H),7.40-7.33 (m, 2H), 6.79-6.72 (m, 1H), 6.49-6.45 (m, 1H), 6.13 (s, 1H),3.34-3.31 (m, 1H), 3.09-3.07 (d, 2H), 2.40-2.36 (m, 1H), 2.17 (s, 6H),1.81-1.76 (m, 1H), 0.97 (d, 3H), 0.85 (d, 2H), 0.66 (m, 3H), 0.61 (s,2H); LCMS: m/z = 504.4 (M + H)⁺; HPLC: 98.59%, rt: 4.42 min. 44

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.77 (s, 1H), 10.44 (s, 1H),8.60 (s, 1H), 8.27 (d, 1H), 8.05 (d, 1H), 7.67 (s, 1H), 7.56 (d, 1H),7.41-7.35 (m, 2H), 6.81-6.77 (m, 1H), 6.47 (d, 1H), 6.13 (s, 1H),3.60-3.58 (m, 5H), 3.11 (d, 2H), 2.67-2.66 (m, 1H), 2.38 (s, 4H),1.81-1.79 (m, 1H), 0.97 (d, 3H), 0.86 (d, 2H), 0.67 (d, 3H), 0.60 (s,2H); LCMS: m/z = 529.40 (M + H)⁺; HPLC: 95.50%, rt: 4.56 min. 45

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02-11.98 (brs, 1H), 10.77 (s, 1H), 10.43(s, 1H), 8.62 (s, 8.27 (d, 1H), 8.16 (s, 1H), 8.07 (d, 1H), 7.69 (s,1H), 7.56 (d, 1H), 7.43-7.35 (m, 1H), 6.85-6.80 (m, 1H), 6 48 (d, 1H),6.11 (s, 1H), 5.30-5.10 (m, 1H), 3.90-3.89 (m, 1H), 2.88-2.79 (m, 2H),2.70-2.59 (m, 2H), 2.33-2.32 (m, 1H), 2.21-2.09 (m, 2H), 1.82-1.78 (m,2H), 1.41 (d, 3H), 0.88-0.86 (m, 2H), 0.62-0.59 (m, 2H); LCMS: m/z =503.60 (M + H)⁺; HPLC: 92.66%, rt: 4.11 min. 46

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02-11.98 (brs, 1H), 10.77 (s, 1H), 10.43(s, 1H), 8.62 (s, 1H), 8.27 (d, 1H), 8.16 (s, 1H), 8.07 (d, 1H), 7.69(s, 1H), 7.56 (d, 1H), 7.43-7.35 (m, 1H), 6.85-6.80 (m, 1H), 6.48 (d,1H), 6.11 (s, 1H), 5.30-5.10 (m, 1H), 3.90-3.89 (m, 1H), 2.88-2.79 (m,2H), 2.70-2.59 (m, 2H), 2.33-2.32 (m, 1H), 2.21-2.09 (m, 2H), 1.82-1.78(m, 2H), 1.41 (d, 3H), 0.88-0.86 (m, 2H), 0.62-0.59 (m, 2H); LCMS: m/z =503.30 (M + H)⁺; HPLC: 95.38%, rt: 5.41 min. 47

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02-11.98 (brs, 1H), 10.77 (s, 1H), 10.43(s, 1H), 8.62 (s, 1H), 8.27 (d, 1H), 8.16 (s, 1H), 8.07 (d, 1H), 7.69(s, 1H), 7.56 (d, 1H), 7.43-7.35 (m, 1H), 6.85-6.80 (m, 1H), 6.48 (d,1H), 6.11 (s, 1H), 5.30-5.10 (m, 1H), 3.90-3.89 (m, 1H), 2.88-2.79 (m,2H), 2.70-2.59 (m, 2H), 2.33-2.32 (m, 1H), 2.21- 2.09 (m, 2H), 1.82-1.78(m, 2H), 1.41 (d, 3H), 0.88-0.86 (m, 2H), 0.62-0.59 (m, 2H); LCMS: m/z =503.30 (M + H)⁺; HPLC: 97.79%, rt: 5.94 min.; Chiral HPLC: 98.06%, rt:10.20 min. (Isomer-1 of compound-46) 48

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02-11.98 (brs, 1H), 10.77 (s, 1H), 10.43(s, 1H), 8.62 (s, 1H), 8.27 (d, 1H), 8.16 (s, 1H), 8.07 (d, 1H), 7.69(s, 1H), 7.56 (d, 1H), 7.43-7.35 (m, 1H), 6.85-6.80 (m, 1H), 6.48 (d,1H), 6.11 (s, 1H), 5.30-5.10 (m, 1H), 3.90-3.89 (m, 1H), 2.88-2.79 (m,2H), 2.70-2.59 (m, 2H), 2.33-2.32 (m, 1H), 2.21- 2.09 (m, 2H), 1.82-1.78(m, 2H), 1.41 (d, 3H), 0.88-0.86 (m, 2H), 0.62-0.59 (m, 2H); LCMS: m/z =503.30 (M + H)⁺; HPLC: 95.92%, rt: 5.94 min.; Chiral HPLC: 97.74%, rt:15.18 min. (Isomer-2 of compound-46) 49

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02-11.98 (brs, 1H), 10.77 (s, 1H), 10.43(s, 1H), 8.62 (s, 1H), 8.27 (d, 1H), 8.16 (s, 1H), 8.07 (d, 1H), 7.69(s, 1H), 7.56 (d, 1H), 7.43-7.35 (m, 1H), 6.85-6.80 (m, 1H), 6.48 (d,1H), 6.11 (s, 1H), 5.30-5.10 (m, 1H), 3.90-3.89 (m, 1H), 2.88-2.79 (m,2H), 2.70-2.59 (m, 2H), 2.33-2.32 (m, 1H), 2.21- 2.09 (m, 2H), 1.82-1.78(m, 2H), 1.41 (d, 3H), 0.88-0.86 (m, 2H), 0.62-0.59 (m, 2H); LCMS: m/z =503.30 (M + H)⁺; HPLC: 97.79%, rt: 5.94 min. 50

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02-11.98 (brs, 1H), 10.77 (s, 1H), 10.43(s, 1H), 8.62 (s, 1H), 8.27 (d, 1H), 8.16 (s, 1H), 8 07 (d, 1H), 7.69(s, 1H), 7.56 (d, 1H), 7.43-7.35 (m, 1H), 6.85-6.80 (m, 1H), 6.48 (d,1H), 6.11 (s, 1H), 5.30-5.10 (m, 1H), 3.90-3.89 (m, 1H), 2.88-2.79 (m,2H), 2.70-2.59 (m, 2H), 2.33-2.32 (m, 1H), 2.21- 2.09 (m, 2H), 1.82-1.78(m, 2H), 1.41 (d, 3H), 0.88-0.86 (m, 2H), 0.62-0.59 (m, 2H); LCMS: m/z =503.30 (M + H)⁺; HPLC: 98.31%, rt: 5.97 min; Chiral HPLC: 98.56%, rt:10.44 min. (Isomer-1 of compound-49) 51

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02-11.98 (brs, 1H), 10.77 (s, 1H), 10.43(s, 1H), 8.62 (s, 1H), 8.27 (d, 1H), 8.16 (s, 1H), 8.07 (d, 1H), 7.69(s, 1H), 7.56 (d, 1H), 7.43-7.35 (m, 1H), 6.85-6.80 (m, 1H), 6 48 (d,1H), 6.11 (s, 1H), 5.30-5.10 (m, 1H), 3.90-3.89 (m, 1H), 2.88-2.79 (m,2H), 2.70-2.59 (m, 2H), 2.33-2.32 (m, 1H), 2.21- 2.09 (m, 2H), 1.82-1.78(m, 2H), 1.41 (d, 3H), 0.88-0.86 (m, 2H), 0.62-0.59 (m, 2H); LCMS: m/z =503.60 (M + H)⁺; HPLC: 97.48%, rt: 5.48 min. Chiral HPLC: 97.95%, rt:20.50 min. (Isomer-2 of compound-49) 52

¹HNMR (DMSO-d₆, 400 MHz): δ 12.03 (s, 1H), 10.74 (s, 1H), 10.42 (s, 1H),8.62 (s, 1H), 8.27 (d, 1H), 8.07 (d, 1H), 7.69 (s, 1H), 7.56 (d, 1H),7.43-7.35 (m, 2H), 6.88-6.81 (m, 1H), 6.50 (d, 1H), 6.13 (s, 1H),3.90-3.87 (m, 1H), 3.24 (s, 2H), 2.50 (m, 4H), 1.82-1.77 (m, 1H), 1.70(m, 4H), 1.41 (d, 3H), 0.87-0.85 (d, 2H), 0.61-0.60 (d, 2H); LCMS: m/z =485.64 (M + H)⁺; HPLC: 96.15%, rt: 8.45 min. 53

¹HNMR (DMSO-d₆, 400 MHz): δ 12.03 (s, 1H), 10.74 (s, 1H), 10.42 (s, 1H),8.62 (s, 1H), 8.27 (d, 1H), 8.07 (d, 1H), 7.69 (s, 1H), 7.56 (d, 1H),7.43-7.35 (m, 2H), 6.88-6.81 (m, 1H), 6.50 (d, 1H), 6.13 (s, 1H),3.90-3.87 (m, 1H), 3.24 (s, 2H), 2.50 (m, 4H), 1.82-1.77 (m, 1H), 1.70(m, 4H), 1.41 (d, 3H), 0.87-0.85 (d, 2H), 0.61-0.60 (d, 2H); LCMS: m/z =485.64 (M + H)⁺; HPLC: 94.40%, rt: 5.95 min.; Chiral HPLC: 97.27%, rt:13.51 min. (Isomer-1 of compound-52) 54

¹HNMR (DMSO-d₆, 400 MHz): δ 12.03 (s, 1H), 10.74 (s, 1H), 10.42 (s, 1H),8.62 (s, 1H), 8.27-8.24 (d, 1H), 8.07-8.02 (d, 1H), 7.69 (s, 1H),7.57-7.55 (d, 1H), 7.43-7.35 (m, 2H), 6.89-6.82 (m, 1H), 6.50 (d, 1H),6.13 (s, 1H), 3.91-3.88 (m, 1H), 3.24 (s, 2H), 2.50 (m, 4H), 1.82-1.77(m, 1H), 1.70 (m, 4H), 1.41-1.40 (d, 3H), 0.87- 0.85 (d, 2H), 0.61-0.60(d, 2H); LCMS: m/z = 485.64 (M + H)⁺; HPLC: 94.04%, rt: 5.97 min.;Chiral HPLC: 95.43%, rt: 16.67 min. (Isomer-2 of compound-52) 55

¹HNMR (DMSO-d₆, 400 MHz): δ 10.77 (s, 1H), 10.43 (s, 1H), 8.62 (s, 1H),8.28 (d, 1H), 8.15 (m, 1H), 8.06 (d, 1H), 7.69 (s, 1H), 7.56 (d, 1H),7.43-7.35 (m, 2H), 6.85-6.80 (m, 1H), 6.47 (d, 1H), 6.13 (s, 1H),3.91-3.87 (m, 1H), 3.25 (d, 2H), 2.52-2.32 (m, 4H), 1.82-1.78 (m, 1H),1.41 (d, 3H), 0.99-0.97 (m, 6H), 0.86 (d, 2H), 0.62-0.60 (m, 2H); LCMS:m/z = 487.6 (M + H)⁺; HPLC: 97.05%, rt: 4.10 min. 56

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.77 (s, 1H), 10.46 (s, 1H),8.61 (s, 1H), 8.29-8.21 (m, 1H), 8.06 (d, 1H), 7.68 (s, 1H), 7.57 (d,1H), 7.44-7.36 (m, 2H), 6.84-6.77 (m, 1H), 6.44 (d, 1H), 6.13 (s, 1H),3.06 (d, 2H), 2.33 (s, 1H), 2.17 (s. 6H), 1.81-1.78 (m, 1H), 0.99-0.97(d, 3H), 0.86 (d, 2H), 0.67 (d, 3H), 0.62-0.59 (m, 2H); LCMS: m/z =487.6 (M + H)⁺; HPLC: 95.92%, rt: 4.35 min. 57

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02(s, 1H), 10.78 (s, 1H), 10.43 (s, 1H),8.63 (d, 1H), 8.28 (d, 1H), 8.08 (dd, 1H), 7.70 (s, 1H), 7.57 (d, 1H),7.44-7.40 (m, 1H), 7.38-7.36 (m, 1H), 6.84-6.77 (m, 1H), 6.56-6.45 (m,1H), 6.14 (s, 1H), 4.73-4.59 (m, 1H), 3.93-3.88 (m, 1H), 3.17-3.16 (m,2H), 2.78-2.67 (m, 2H), 2.45-2.25 (m, 2H), 1.85- 1.78 (m, 3H), 1.74-1.46(m, 2H), 1.42 (d, 3H), 0.87 (d, 2H), 0.61 (d, 2H); LCMS: m/z = 517.6(M + H)⁺; HPLC: 99.22%, rt: 3.40 min. 58

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.48 (s, 1H), 10.17 (s, 1H),8.65 (d, 1H), 8.05 (s, 1H), 7.91-7.85 (m, 2H), 7.43-7.42 (m, 2H),6.81-6.76 (m, 1H), 6.55-6.52 (m, 1H), 6.14 (s, 1H), 3.94-3.92 (m, 1H),3.62-3.60 (m, 4H), 3.16-3.13 (m, 2H), 2.40 (s, 4H), 1.82-1.79 (m, 1H),1.43 (d, 3H), 0.87 (d, 2H), 0.62 (d, 2H); LCMS: m/z = 519.2 (M + H)⁺;HPLC: 98.82%, rt: 5.92 min. 59

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.43 (s, 1H), 10.36 (s, 1H),8.21-8.18 (d, 1H), 8.12-8.07 (m, 1H), 7.59-7.58 (m, 1H), 7.44-7.38 (m,3H), 6.85-6.78 (m, 1H), 6.46-6.42 (d, 1H), 6.11 (s, 1H), 3.90-3.87 (m,1H), 3.61-3.58 (m, 4H), 3.16-3.11 (m, 2H), 2.38-2.32 (m, 4H), 1.88-1.77(m, 1H), 1.41-1.39 (m, 3H), 0.89-0.84 (m, 2H), 0.62-0.58 (m, 2H); LCMS:m/z = 519 (M + H)⁺; HPLC: 98.28%, rt: 3.82 min. 60

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.43 (s, 1H), 10.36 (s, 1H),8.21-8.18 (d, 1H), 8.55-8.54 (m, 1H), 8.35 (s, 1H), 7.66 (s, 1H),7.55-7.53 (m, 1H), 7.47-7.40 (m, 2H), 6.83-6.76 (m, 1H), 6.34-6.30 (d,1H), 6.15 (s, 1H), 3.95-3.93 (m, 1H), 3.61-3.58 (m, 4H), 3.16-3.11 (m,2H), 2.38-2.32 (m, 4H), 1.88-1.77 (m, 1H), 1.41- 1.39 (m, 3H), 0.89-0.84(m, 2H), 0.62-0.58 (m, 2H); LCMS: m/z = 501.1 (M + H)⁺; HPLC: 95.28%,rt: 5.61 min. 61

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.43 (s, 1H), 10.36 (s, 1H),7.93 (s, 1H), 7.68-7.66 (d, 1H), 7.62 (s, 1H), 7.47-7.35 (m, 4H),7.31-7.29 (d, 1H), 6.78-6.71 (m, 1H), 6.32-6.28 (d, 1H), 6.14 (s, 1H),3.91-3.88 (m, 1H), 3.61- 3.58 (m, 4H), 3.17-3.11 (m, 2H), 2.39-2.32 (m,4H), 1.82-1.75 (m, 1H), 1.41-1.36 (m, 3H), 0.88-0.86 (m, 2H), 0.61-0.60(m, 2H); LCMS: m/z = 500.1 (M + H)⁺; HPLC: 95.40%, rt: 6.08 min. 62

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.82 (s, 1H), 10.42 (s, 1H),8.64-8.63 (d, 1H), 8.31- 8.29 (d, 1H), 8.10-8.08 (m, 1H), 7.71 (s, 1H),7.59-7.57 (d, 1H), 7.45-7.41 (m, 1H), 7.38-7.36 (d, 1H), 6.92-6.85 (m,1H), 6.49-6.45 (d, 1H), 6.13 (s, 1H), 3.92-3.90 (m, 1H), 3.44 (s, 5H),2.55 (s, 3H), 1.84-1.80 (m, 1H), 1.44-1.42 (m, 3H), 0.89-0.86 (m, 2H),0.64-0.60 (m, 2H); LCMS: m/z = 475.6 (M + H)⁺; HPLC: 95.10%, rt: 4.01min. 63

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.48 (s, 1H), 10.41 (s, 1H),8.56 (s, 1H), 8.09-8.06 (m, 1H), 7.76 (s, 1H), 7.64-7.63 (d, 1H),7.46-7.39 (m, 2H), 6.81-6.74 (m, 1H), 6.38-6.34 (d, 1H), 6.14 (s, 1H),3.95-3 88 (m, 1H), 3.61-3.59 (m, 4H), 3.16-3.13 (m, 2H), 2.40 (s, 4H),1.84-1.79 (m, 1H), 1.43-1.42 (d, 3H), 0.88-0.86 (m, 2H), 0.62-0.60 (m,2H); LCMS: m/z = 519.60 (M + H)⁺; HPLC: 95.10%, rt: 5.79 min. 64

¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.48 (s, 1H), 10.21 (s, 1H),8.68-8.63 (m, 1H), 8.04 (s, 1H), 7.90-7.86 (m, 2H), 7.88-7.85 (m, 2H),7.42-7.41 (d, 2H), 6.85-6.81 (m, 1H), 6.55-6.52 (d, 1H), 6.14 (s, 1H),5.61-5.21 (m, 1H), 3.93-3.91 (m, 1H), 2.85-2 81 (m, 2H), 2.26-2.21 (m,2H), 2.01-1.80 (m, 3H), 1.42-1.40 (d, 3H), 0.88-0.86 (m, 2H), 0.61-0.60(m, 2H); LCMS: m/z = 520.30 (M + H)⁺; HPLC: 95.27%, rt: 6.29 min. 65

¹HNMR (DMSO-d₆, 400 MHz): δ 12 01 (s, 1H), 10.41 (s, 1H), 9.47 (s, 1H),8.17-8.15 (d, 1H), 7.60 (s, 1H), 7.55-7.53 (d, 1H), 7.41-7.37 (m, 1H),7.33-7.32 (m, 1H), 7.25-7.21 (d, 1H), 7.20-7.18 (d, 1H), 6.80-6.72 (m,1H), 6.27-6.22 (d, 1H), 6.13 (s, 1H), 5.74-5.71 (d, 1H), 3.93-3.86 (m,3H), 2.61-2.35 (m, 1H), 1.86-1.72 (m, 1H), 1.46 (d, 3H), 0.88-0.86 (m,2H), 0.62-0.64 (m, 2H), LCMS: m/z = 431.5 (M + H)⁺; HPLC: 95.38%, rt:4.20 min. 66

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.4 (s, 1H), 9.53 (s, 1H),7.65- 7.61 (m, 2H), 7.51-7.49 (d, 2H), 7.47-7.43 (d, 1H), 7.41-7.38 (m,1H), 7.36-7.33 (d, 1H), 6.62-6.53 (m, 1H), 6.28-6.24 (s, 1H), 6.10 (s,1H), 5.77-5.74 (d, 1H), 3.91-3.85 (m, 1H), 2.32-2.29 (s, 3H), 1.82-1.78(m, 1H), 1.42-1.40 (d, 3H), 0.88-0.86 (m, 2H), 0.62-0.60 (m, 2H), LCMS:m/z = 415.1 (M + H)⁺; HPLC: 95.38%, rt: 4.47 min. 67

¹HNMR (DMSO-d₆, 400 MHz): δ 12.10 (s, 1H), 10.41 (s, 1H), 9.51 (s, 1H),7.60 (s, 1H), 7.51-7.42 (d, 1H), 7.38-7.32 (m, 4H), 6.62 (s, 1H),6.65-653 (m, 1H), 6.14-6.13 (d, 1H), 5.76-5.73 (m, 1H), 3.32-3.22 (m,1H) 2.62-2.51 (s, 3H), 2.53-2.24 (s, 3H), 1.81-1.70 (m, 1H), 1.47 (d,3H), 0.88-0.86 (m, 2H), 0.62-0.64 (m, 2H), LCMS: m/z = 429.2 (M + H)⁺;HPLC: 99.38%, rt: 4.48 min. 68

¹HNMR (DMSO-d₆, 400 MHz): δ 12.10 (s, 1H), 10.82 (s, 1H), 10.41 (s, 1H),8.62-8.61 (d, 1H), 8.29-8.27 (d, 1H), 8.08-8.05 (m, 1H), 7.70 ( s, 1H),7.57-7.55 (d, 1H), 7.43-7.35 (m, 2H), 6.87-6.80 (m, 1H), 6.51-6.47 (d,1H), 6.13 (s, 1H), 3.91-3.89 (m, 1H), 3.45-3.42 (d, 2H), 3.24 (s, 3H),3.18-3.15 (d. 2H), 2.53-2.51 (d, 2H), 2.20 (s, 3H), 1.82-179 (m, 1H),1.43-1.41 (d, 3H), 0.86-0.85 (m, 2H), 0.62-0.61 (m, 2H) LCMS: m/z =503.30 (M + H)⁺; HPLC: 97.87%, rt: 7.07 min. 69

¹HNMR (DMSO-d₆, 400 MHz): δ 12.10 (s, 1H), 11.79 (s, 1H), 10.41 (s, 1H),8.60-8.59 (m, 1H), 8.17-8.15 (d, 1H), 8.06-8.04 (m, 1H), 7.09 (s, 1H),7.67 (s, 1H), 7.57-7.53 (m, 2H), 7.42-7.33 (m, 2H), 7.10-7.07 (d, 1H),6.96 (s, 1H), 6.14-6.07 (m, 2H), 3.91-3.84 (m, 1H), 3.31-3.29 (d, 2H),1.80-1.40 (m, 1H), 1.40-1.39 (d, 3H), 0.87-0.81 (m, 2H), 0.59-0.56 (m,2H) LCMS: m/z = 482.23 (M + H)⁺; HPLC: 99.21%, rt: 5.91 min. 70

¹HNMR (DMSO-d₆, 400 MHz): δ 12.10 (s, 1H), 10.78 (s, 1H), 10.41 (s, 1H),8.62-8.61 (d, 1H), 8.29- 8.27 (d, 1H), 8.08-8.05 (m, 1H), 7.69 (s, 1H),7.57-7.55 (d, 1H), 7.43-7.39 (m, 1H), 7.40-7.35 (d, 1H), 6.87-6.83 (m,1H), 6.47- 6.43 (d, 1H), 6.13 (s, 1H), 3.91- 3.89 (m, 1H), 3.67-3.64 (m,1H), 3.34 (s, 3H), 3.28-3.12 (m, 2H), 3.07-2.98 (m, 1H), 2.64-2.52 (m,2H), 2.19-2.17 (m, 1H), 1.85-180 (m, 2H), 1.67-1.64 (m, 2H), 1.50-1.48(m, 1H), 1.43-1.41 (d, 3H), 0.86-0.85 (m, 2H), 0.62-0.61 (m, 2H) LCMS:m/z = 529.35 (M + H)⁺; HPLC: 98.94%, rt: 6.06 min. 71

¹HNMR (DMSO-d₆, 400 MHz): δ 11.01 (s, 1H), 10.53 (s, 1H), 9.93 (s, 1H),8.65-8.64 (d, 1H), 8.29- 8.27 (d, 1H), 8.12-8.09 (m, 1H), 7.70 (s, 1H),7.58-7.56 (d, 1H), 7.44-7.36 (m, 2H), 6.89-6.85 (m, 1H), 6.66-6.62 (d,1H), 6.11 (s, 1H), 3.99-3.97 (m, 1H), 3.94-3.90 (m, 2H), 3.71 (s, 1H),3.66-3.56 (m, 2H), 3.52-3.50 (m, 1H), 3.34 (s, 3H), 3.16-3.14 (m, 1H),2.13-2.01 (m, 1H), 2.00-1.88 (m, 1H), 1.86-1.80 (m, 3H), 1.43-1.42 (d,3H), 0.89-0.84 (m, 2H), 0.62-0.58 (m, 2H); LCMS: m/z = 529.30 (M + H)⁺;HPLC: 95.22%, rt: 5.36 min. (Isomer-1 of compound-70) 72

¹HNMR (DMSO-d₆, 400 MHz): δ 11.01 (s, 1H), 10.53 (s, 1H), 9.93 (s, 1H),8.65-8.64 (d, 1H), 8.29- 8.27 (d, 1H), 8.12-8.09 (m, 1H), 7.70 (s, 1H),7.58-7.56 (d, 1H), 7.44-7.36 (m, 2H), 6.89-6.85 (m, 1H), 6.66-6.62 (d,1H), 6.11 (s, 1H), 3.99-3.97 (m, 1H), 3.94-3.90 (m, 2H), 3.71 (s, 1H),3.66-3.56 (m, 2H), 3.52-3.50 (m, 1H), 3.34 (s, 3H), 3.16-3.14 (m, 1H),2.13-2.01 (m, 1H), 2.00-1.88 (m, 1H), 1.86-1.80 (m, 3H), 1.43-1.42 (d,3H), 0.89-0.84 (m, 2H), 0.62-0.58 (m, 2H); LCMS: m/z = 529.30 (M + H)⁺;HPLC: 95.02%, rt: 5.61 min. (Isomer-2 of compound-70) 73

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.40 (s, 1H), 10.26 (s, 1H),7.54 (s, 1H), 7.42 (s, 1H), 7.31-7.22 (m, 5H), 6.48-6.42 (m, 1H),6.30-6.25 (d, 1H), 6.13 (s, 1H), 5.74-5.71 (d, 1H), 3.86-3.84 (m, 1H),3.72-3.70 (d, 3H), 2.61-2.35 (m, 1H), 1.39-1.23 (d, 3H), 0.88-0.86 (m,2H), 0.62-0.64 (m, 2H), LCMS: m/z = 430.51 (M + H)⁺; HPLC: 95.75%, rt:4.07 min. 74

¹HNMR (DMSO-d₆, 400 MHz): δ 12.05 (s, 1H), 10.45 (s, 1H), 8.78-8.77 (m.2H), 8.02-8.00 (m, 1H), 7.68 (s, 1H), 7.57-7.55 (m, 1H), 7.45-7.37 (m,3H), 6.38-6.31 (m, 1H), 6.16-6.12 (m, 2H), 5.66-5.63 (m, 1H), 4.49-4.48(m, 2H), 3.92-3.90 (m, 1H), 1.82-1.78 (m, 1H), 1.42-1.41 (m, 3H),0.88-0.86 (m, 2H), 0.61-0.60 (m, 2H); LCMS: m/z = 416.3 (M + H)⁺; HPLC:95.62%, rt: 3.80 min. 75

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.41 (s, 1H), 9.52 (s, 1H),7.53 (s, 2H), 7.34-7.32 (m, 3H), 7.16-7.13 (d, 2H), 6.61-6.52 (m, 1H),6.28-6.24 (d, 1H), 6.10 (s, 1H), 5.77-5.74 (d, 1H), 3.90-3.81 (m, 1H),2.20 (s, 3H), 1.80-1.70 (m, 1H), 1.39-138 (d, 3H), 0.88-0.86 (m, 2H),0.62-0.64 (m, 2H), LCMS: m/z = 414.5 (M + H)⁺; HPLC: 97.6%, rt: 9.68min. 76

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.41 (s, 1H), 8.22-8.20 (d,2H), 7.64 (s, 1H), 7.53 (s, 1H), 7.50-7.46 (m, 1H), 7.38-7.35 (m, 1H),7.31-7.29 (d, 1H), 6.80-6.74 (m, 1H), 6.34- 6.29 (d, 1H), 6.13 (s, 1H),5.85-5.82 (d, 1H), 4.29-4.24 (m, 2H), 3.89-3.87 (m, 1H), 3.33-3.15 (m,2H), 1.82-1.78 (m, 1H), 1.41-1.40 (d, 3H), 0.88-0.86 (m, 2H), 0.62-0.64(m, 2H), LCMS: m/z = 427.15 (M + H)⁺; HPLC: 97.60%, rt: 4.53 77

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 11.89 (s, 1H), 10.43 (s, 1H),8.62-8.61 (d, 1H), 8.31-8.27 (m, 1H), 8.08-8.05 (m, 1H), 7.70 (s, 1H),7.58-7.56 (d, 1H), 7.44-7.36 (m, 2H), 6.89- 6.85 (m, 1H), 6.48-6.44 (d,1H), 6.11 (s, 1H), 3.99-3.87 (m, 1H), 3.71-3.66 (m, 1H), 3.47-3.43 (m,1H), 3.34 (s, 3H), 3.20-3.15 (m, 2H), 3.09-3.05 (m, 2H), 2.72-2.67 (m,1H), 2.37-2.33 (m, 2H), 1.80-1.75 (m, 2H), 1.43-1.41 (m, 3H), 0.89-0.84(m, 2H), 0.62-0.58 (m, 2H); LCMS: m/z = 547.30 (M + H)⁺; HPLC: 95.24%,rt: 6.08 min. 78

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 11.89 (s, 1H), 10.43 (s, 1H),8.62-8.61 (d, 1H), 8.31-8.27 (d, 1H), 8.08-8.05 (m, 1H), 7.70 (s, 1H),7.58-7.56 (d, 1H), 7.44-7.36 (m, 2H), 6.89- 6.79 (m, 1H), 6.48-6.44 (d,1H), 6.11 (s, 1H), 3.99-3.87 (m, 1H), 3.43-3.40 (m, 3H), 2.76-2.66 (m,4H), 2.32 (s, 1H), 1.97-1.92 (m, 1H), 1.83-1.78 (m, 1H), 1.43-1.41 (m,3H), 0.89-0.84 (m, 2H), 0.62-0.58 (m, 2H); LCMS: m/z = 510.20 (M + H)⁺;HPLC: 95.16%, rt: 5.96 min. 79

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 11.04 (s, 1H), 10.32 (s, 1H),9.40 (s, 1H), 8.92 (s, 1H), 8.10 (s, 1H), 7.97-7.98 (d, 1H), 7.46-7.46(m, 2H), 6.89-6.79 (m, 1H), 6.48-6.44 (d, 1H), 6.11 (s, 1H), 5.88-5.85(d, 1H), 3.99-3.87 (m, 1H), 2.08-1.78 (m, 1H), 1.43-1.41 (m, 3H),0.89-0.84 (m, 2H), 0.62-0.58 (m, 2H); LCMS: m/z = 402.80 (M + H)⁺; HPLC:95.62%, rt: 3.46 min. 80

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.41 (s, 1H), 9.96 (s, 1H),8 14-8.10 (m, 1H), 7.69 (s, 1H), 7.57-7.54 (m, 2H), 7.48-7.47 (d, 1H),7.46-7.33 (m, 2H), 6.89-6.79 (m, 1H), 6.48-6.44 (d, 1H), 6.11 (s, 1H),5.28-5.14 (m, 1H), 3.99-3.87 (m, 1H), 3.28-3.26 (m, 2H), 2.90-2.80 (m,2H), 2.70-2.66 (m, 1H), 2.35-2.32 (m, 2H), 2.20-2.08 (m, 1H), 1.83-1.78(m, 2H), 1.43-1.41 (m, 3H), 0.89-0.84 (m, 2H), 0.62-0.58 (m, 2H); LCMS:m/z = 520.31 (M + H)⁺; HPLC: 91.57%, rt: 6.11 min. 81

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 11.89 (s, 1H), 10.43 (s, 1H),8.62-8.61 (d, 1H), 8.29-8.27 (d, 1H), 8.08-8.05 (m, 1H), 7.70 (s, 1H),7.58-7.56 (d, 1H), 7.44-7.36 (m, 2H), 6.89-6.85 (m, 1H), 6.48-6.44 (d,1H), 6.11 (s, 1H), 4.44 (s, 4H), 4.15-4.01 (m, 3H), 3.96-3.93 (m, 1H),3.92 (s, 3H), 3.60-3.43 (m, 1H), 2.09-2.05 (m, 1H), 1.82-1.43 (m, 1H),1.43-1.41 (m, 3H), 0.89-0.84 (m, 2H), 0.62-0.58 (m, 2H); LCMS: m/z =543.25 (M + H)⁺; HPLC: 95.52%, rt: 6.07 min. 82

¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 11.89 (s, 1H), 10.43 (s, 1H),8.62-8.61 (d, 1H), 8.31- 8.27 (d, 1H), 8.08-8.05 (m, 1H), 7.70 (s, 1H),7.58-7.56 (d, 1H), 7.44-7.36 (m, 2H), 6.89-6.79 (m, 1H), 6.48-6.44 (d,1H), 6.11 (s, 1H), 3.99-3.87 (m, 1H), 3.64-3.61 (m, 1H), 3.10-3.02 (m,2H), 2.74- 2.68 (m, 1H), 2.67-2.62 (m, 2H), 2.28-2.22 (m, 1H), 2.01-1.94(m, 1H), 1.84-1.68 (m, 3H), 1.61-1.60 (m, 1H), 1.43-1.41 (d, 3H),0.89-0.84 (m, 2H), 0.62-0.58 (m, 2H); LCMS: m/z = 524.21 (M + H)⁺; HPLC:93.58%, rt: 6.07

Example-3: Synthesis of4-acrylamido-N-(3-((5-ethyl-1H-pyrazol-3-yl)amino)phenyl)-benzamide.(Compound-83)

Step-i: Synthesis of tert-butyl5-ethyl-3-((3-nitrophenyl)amino)-1H-pyrazole-1-carboxylate

To a degassed solution of tert-butyl3-amino-5-ethyl-1H-pyrazole-1-carboxylate (synthesized similar tointermediate-1-A) (0.5 g, 2.36 mmol) and 1-bromo-3-nitrobenzene (0.571g, 2.84 mmol) in 1,4-dioxane (20 mL) added Cs₂CO₃ (1.91 g, 5.92 mmol),stirred the reaction mass for 10 minutes at RT and degassed further for10 min and added Xantphos (0.136 g, 0.236. mmol) and Pd₂(dba)₃ (0.108 g,0.118 mmol). The reaction mass was heated for 4 h at 100° C. in a sealedtube. The reaction mass was cooled and diluted with water and ethylacetate. The organic layer was separated and the aqueous layer wasextracted again with ethyl acetate (2×20 mL). The combined organic layerwas dried over anhydrous sodium sulphate and concentrated under vacuum.The crude compound was purified by silica gel column chromatography byeluting with 15% ethyl acetate-hexane to afford the title compound (0.2g, 35%). LCMS: m/z=333.10 (M+H)⁺.

Step-ii: Synthesis of tert-butyl3-((3-aminophenyl)amino)-5-ethyl-1H-pyrazole-1-carboxylate

tert-butyl-5-ethyl-3-((3-nitrophenyl)amino)-1H-pyrazole-1-carboxylate(0.2 g, 0.60 mmol) was taken in ethanol, 10% Pd/C (0.05 g) was added andreaction mass was stirred at RT under H₂ pressure (40 Psi) for 4 h in aParr shaker. Reaction mixture was filtered on a celite bed, washed withethanol and the filtrate was concentrated under vacuum to get the titlecompound. (0.13 g, 49%) LCMS: m/z=302.8 (M+H)⁺.

Step-iii: Synthesis of tert-butyl3-((3-(4-acrylamidobenzamido)phenyl)amino)-5-ethyl-1H-pyrazole-1-carboxylate

To a solution of 4-acrylamidobenzoic acid (0.098 g (intermediate-11),0.52 mmol) in DMF (4 mL), was added HATU (0.245 g, 0.64 mmol) followedby DIPEA (0.2 mL, 1.05 mmol) and finally added tert-butyl3-((3-aminophenyl)amino)-5-ethyl-1H-pyrazole-1-carboxylate (0.13 g,0.430 mmol). The reaction mixture was stirred for 12 h at roomtemperature. The reaction mixture was quenched with ice-water anddiluted with ethyl acetate. The aqueous layer was separated andextracted with ethyl acetate (2×25 mL). The combined organic phase waswashed with brine, dried over Na₂SO₄, filtered and concentrated. (0.13g, 90%). LCMS: m/z=476.2 (M+H)⁺.

Step-iv: Synthesis of4-acrylamido-N-(3-((5-ethyl-1H-pyrazol-3-yl)amino)phenyl)benzamide

To a solution oftert-butyl-3-((3-(4-acrylamidobenzamido)phenyl)amino)-5-ethyl-1H-pyrazole-1-carboxylate(0.13 g, 0.33 mmol) in DCM (3 mL), TFA (1 mL) was added at 0° C. Thereaction mass was stirred at room temperature for 2 h. The reaction masswas concentrated under vacuum to afford crude compound. The crudecompound was purified by silica gel column chromatography by elutingwith 10% methanol-DCM, further purified by Preparative HPLC (Method:Column: X-BRIDGE PREP C18 5 MICRON OBD (19 mm×150 mm), Mobile phase:0.01% NH₄OH:Acetonitrile) to afford the title compound (0.030 g, 25%).¹HNMR (DMSO-d₆, 400 MHz): δ 11.5 (s, 1H), 10.38 (s, 1H), 9.93 (s, 3H),8.23 (s, 1H), 7.91 (d, 1H), 7.76 (d, 1H), 7.64 (s, 1H), 7.05-6.98 (m,3H), 6.46-6.40 (m, 1H), 6.29-6.24 (d, 1H), 5.78 (d, 1H), 5.62 (s, 1H),2.52-2.50 (m, 2H), 1.16-1.12 (t, 3H); LCMS: m/z=376.10 (M+H)⁺; HPLC:92.00%, rt: 3.28 min.

Example-4: Synthesis of(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)-but-2-enoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanamide(Compound-84)

Step-i: Synthesis of tert-butyl4-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

To a degassed solution of tert-butyl3-(2-(3-bromophenyl)propanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate(0.45 g, 1.03 mmol) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(0.42 g, 1.37 mmol) in 1,4-dioxane (20 mL) and water (1 mL) K₂CO₃ (0.45g, 3.26 mmol) was added. The reaction mass was stirred for 10 minutesand degassed further for 10 min and added PdCl₂(dppf).DCM (0.044 g, 0.05mmol). The reaction mass was heated for 5 h at 100° C. in a sealed tube.The reaction mass was cooled to room temperature and diluted with waterand ethyl acetate. The separated organic layer was dried over anhydroussodium sulphate and concentrated under reduced pressure, purified thecompound by combi flash column by eluting with 70% ethyl acetate-hexanesystem to afford the title compound (0.3 g, 66%) LCMS: m/z=437.2 (M+H)⁺.

Step-ii: Synthesis ofN-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanamide

TFA (1 mL) was slowly added to a stirred solution of tert-butyl4-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(0.1 g, 0.22 mmol) in dry DCM (10 mL) under argon atmosphere at 0° C.The resulting reaction mixture was allowed to warm to room temperatureand stirred for 1 h. After completion of the reaction, excess solventswere removed under reduced pressure to dryness to afford the titlecompound (0.13 g title compound as TFA salt). LCMS: m/z=337.1 (M+H)⁺.

Step-iii: Synthesis of(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanamide

To a solution of (E)-4-(dimethylamino)but-2-enoic acid (0.063 g, 0.37mmol) in DMF (5 mL) was added HATU (0.21 g, 0.55 mmol) at 0° C. followedby DIPEA (0.14 mL, 1.11 mmol) and finally addedN-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanamide(0.17 g, 0.37 mmol). The reaction mass was stirred for 1 h at roomtemperature. The reaction mixture was quenched with ice-water anddiluted with ethyl acetate. The aqueous layer was separated andextracted with ethyl acetate (2×25 mL). The combined organic phase waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure and further purified by preparative HPLC condition(Column: X-bridge prep C18 5u OBD (19*150 mm), Mobile phase:Ammonia-water) to afford the title compound as free base (0.02 g, 12%);¹HNMR (DMSO-d₆, 400 MHz): δ 12.02 (s, 1H), 10.38 (s, 1H), 7.44 (s, 1H),7.24-7.27 (m, 3H), 6.59-6.66 (m, 2H), 6.13 (s, 2H), 4.15-4.25 (m, 2H),3.81-3.83 (d, 2H), 3.73-3.74 (m, 2H), 3.4 (s, 1H), 3.03 (s, 2H), 2.14(s, 6H), 1.79-1.82 (m, 1H), 1.36 (d, 3H), 0.87 (d, 2H), 0.6 (d, 2H).LCMS: m/z=448.2 (M+H)⁺; HPLC: 98.28%, rt: 5.92 min.

Example-5: Synthesis of(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)phenyl)propanamide(Compound-85)

Step-i: Synthesis of tert-butyl4-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)piperidine-1-carboxylate

10% Pd/C was added to a degassed solution of tert-butyl4-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(0.12 g, 0.28 mmol) in methanol (10 mL). The reaction mixture wassubjected to hydrogenation at 45 PSi in Parr shaker for 40 minutes. Thereaction mass was filtered through celite bed and washed the celite bedwith methanol. The filtrate was concentrated under reduced pressure toafford the title compound (0.11 g, 87%). LCMS: m/z=439.1 (M+H)⁺.

Step-ii: Synthesis ofN-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(piperidin-4-yl)phenyl)-propanamide

TFA (1 mL) was slowly added to a stirred solution of tert-butyl4-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)piperidine-1-carboxylate(0.11 g, 0.25 mmol) in dry DCM (5 mL) under argon atmosphere at 0° C.The resulting reaction mixture was allowed to warm to room temperatureand stirred for 1 h. After completion of the reaction, excess solventswere removed under reduced pressure to dryness to afford the titlecompound (0.12 g title compound as TFA salt). LCMS: m/z=339.25 (M+H)⁺.

Step-iii: Synthesis of(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)phenyl)propanamide

To a solution of (E)-4-(dimethylamino)but-2-enoic acid (0.063 g, 0.37mmol) in DMF (5 mL) was added HATU (0.21 g, 0.55 mmol) at 0° C. followedby DIPEA (0.14 g, 1.11 mmol) and finally addedN-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(piperidin-4-yl)phenyl)propanamide(0.17 g, 0.37 mmol). The reaction mass was stirred for 1 h at roomtemperature. The reaction mixture was quenched with ice-water anddiluted with ethyl acetate. The aqueous layer was separated andextracted with ethyl acetate (2×25 mL). The combined organic phase waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure and purified by prep HPLC (X bridge C18 (21.2*150 mm),ammonium hydroxide/water-acetonitrile) to afford the title compound(0.021 g, 9.3%). ¹HNMR (DMSO-d₆, 400 MHz): δ 11.98 (s, 1H), 10.33 (s,1H), 7.13-7.21 (m, 3H), 7.05 (d, 1H), 6.51-6.62 (m, 2H), 6.09 (s, 1H),4.53 (d, 1H), 4.11 (d, 1H), 3.75 (d, 1H), 3.09 (t, 1H), 2.98 (d, 2H),2.63-2.75 (m, 2H), 2.11 (s, 6H), 1.75-1.77 (m, 3H), 1.44-1.47 (m, 2H),1.30 (d, 3H), 0.84 (d, 2H), 0.57 (d, 2H); LCMS: m/z=450.0 (M+H)⁺; HPLC:98.00%, rt: 6.44 min.

Example-6: Synthesis ofN-(3′-(2-((5-Methyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)-[1,1′-biphenyl]-4-yl)acrylamide(Compound-86)

Step i: Synthesis of tert-butyl3-amino-5-methyl-1H-pyrazole-1-carboxylate 60% NaH (0.5 g, 20.6 mmol)was added to a stirred solution of 5-methyl-1H-pyrazol-3-amine (2 g,20.6 mmol) in THE (50 mL) at 0° C. over a period of 10 min followed bythe addition of Boc anhydride (4.5 mL, 20.6 mmol). The reaction mass wasstirred at room temperature over a period of 2 h. The reaction mass wasdiluted with ethyl acetate and water. The separated organic layer wasdried over anhydrous sodium sulphate and concentrated under reducedpressure, the residue was purified by combiflash by eluting with 30%ethyl acetate-hexane system to afford the title compound (1.8 g, 80%)LCMS: m/z=198.0 (M+H)⁺.

Step-ii: Synthesis of tert-butyl3-(2-(3-bromophenyl)acetamido)-5-methyl-1H-pyrazole-1-carboxylate

To a solution of 2-(3-bromophenyl)acetic acid (0.5 g, 2.32 mmol) in DCM(20 mL) was added EDCI (0.88 g, 0.4.65 mmol) at 0° C. followed by DIPEA(1.12 mL, 6.97 mmol) and finally added tert-butyl3-amino-5-methyl-1H-pyrazole-1-carboxylate (0.4 g, 2.09 mmol). Thereaction mass was stirred for 12 h at room temperature. The reactionmixture was quenched with ice-water and diluted with DCM. The aqueouslayer was separated and extracted with ethyl acetate (2×25 mL). Thecombined organic phase was washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure and purified by elutingwith 20% ethyl acetate-hexane in combiflash to afford the title compound(0.3 g, 60%). LCMS: m/z=395.9 (M+H)⁺.

Step-iii: Synthesis ofN-(3′-(2-((5-Methyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)-[1,1′-biphenyl]-4-yl)acrylamide

To a degassed solution of tert-butyl3-(2-(3-bromophenyl)acetamido)-5-methyl-1H-pyrazole-1-carboxylate (0.2g, 0.5 mmol) andN-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide(0.166 g, 0.6 mmol) in DMF (2.5 mL) and water (0.5 mL), K₂CO₃ (0.12 g,0.81 mmol) was added. The reaction mass was stirred for 10 minutes anddegassed further for 10 min and added Bis(triphenylphosphine)palladium(II) dichloride (0.017 g, 0.025 mmol). The reaction mass washeated for 5 h at 100° C. in a sealed tube. The reaction mass was cooledand diluted with water and ethyl acetate. The separated organic layerwas dried over anhydrous sodium sulphate and concentrated under reducedpressure and purified by preparative HPLC (Condition: Kinetex Evo, A:0.1% formic acid in H₂O, B: Acetonitrile-methanol) to afford the titlecompound (0.018 g, 20%). ¹HNMR (DMSO-d₆, 400 MHz): δ 11.78 (s, 1H),10.14 (s, 1H), 10.04 (s, 1H), 7.811 (d, 2H), 7.789 (t, 3H), 7.55 (d,1H), 7.438 (t, 1H), 7.33 (d, 1H), 6.53-6.47 (m, 1H), 6.34 (d, 1H), 6.29(s, 1H), 5.80 (d, 1H), 3.71 (s, 2H), 2.22 (s, 3H); LCMS: m/z=361.1(M+H)⁺; HPLC: 96.04%, rt: 3.39 min.

The compounds listed in the below table-3 were prepared by proceduresimilar to the one described in Example-6 with appropriate variations inreactants, quantities of reagents, protections and deprotections,solvents and reaction conditions. The characterization data of thecompounds are also summarized herein the table-3.

TABLE 3 Compound No. Structure Characterization data 87

¹HNMR (DMSO-d₆, 400 MHz): δ 11.99 (s, 1H), 10.43 (s, 1H), 10.27 (s, 1H),7.77 (d, 2H), 7.66-7.60 (m, 3H), 7.50 (d, 1H), 7.38 (t, 1H), 7.32 (d,1H), 6.49-6.42 (m, 1H), 6.30-6.25 (m, 2H), 5.77 (dd, 1H), 3.90 (dd, 1H),2.5 (q, 2H), 1.42 (d, 3H), 1.13 (t, 3H); LCMS: m/z = 389.20 (M + H)⁺;HPLC: 95.10%, rt: 12.02 min. 88

¹HNMR (DMSO-d₆, 400 MHz): δ 12.06 (s, 1H), 10.45 (s, 1H), 10.26 (s, 1H),7.78 (d, 2H), 7.76 (t, 3H), 7.51 (d, 1H), 7.40-7.31 (m, 2H), 6.46-6.42(m, 1H), 6.30-6.25 (m, 2H), 5.77 (dd, 1H), 3.91 (d, 1H), 1.43 (d, 3H),1.22 (s, 9H); LCMS: m/z = 417.1 (M + H)⁺; HPLC: 97.51%, rt: 4.38 min.

Example-7: Synthesis of(E)-N-(3-((1H-Indazol-3-yl)amino)phenyl)-4-(4-(dimethylamino)-but-2-enamido)benzamide(Compound-89)

Step-i: Synthesis of 3-bromo-1H-indazole

Bromine (1.5 g, 9.4 mmol) in 2M NaOH solution (10 mL) was added dropwise to a suspension of indazole (1.5 g, 12.7 mmol) in 2M NaOH solution(23 mL) at ambient temperature. Stirred the reaction mass for 3 h atroom temperature and added sodium bisulfate (0.05 g) followed by theaddition of 2N HCl. The solid precipitated was filtered out and washedwith water, suction dried followed by in Rotavap under reduced pressureto afford the title compound (2 g, 80%). LCMS: m/z=197.1 (M+H)⁺.

Step-i: Synthesis of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

3,4-dihydro-2H-Pyrane (0.42 g, 5 mmol) was added to a solution of3-bromo-1H-indazole (0.5 g, 2.5 mmol) in ethyl acetate (10 mL) withcatalytic amount of PTSA (0.05 g). The resulting reaction mass wasstirred and heated to reflux for 5 h. The reaction mass was neutralizedwith aq. ammonia and diluted with ethyl acetate. The separated organiclayer was dried over anhydrous sodium sulphate and concentrated underreduced pressure and purified by silica gel column chromatography byeluting with 500 ethyl acetate-hexane to afford the title compound (0.4g, 51%) LCMS: m/z=283 (M+3).

Step-iii: Synthesis ofN¹-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)benzene-1,3-diamine

Benzene-1,3-diamine (0.02 g, 0.21 mmol) and3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.05 g, 0.17 mmol)were taken in toluene (15 mL) in a seal tube at room temperature andargon gas was purged for 5-10 min. Then sodium tert-butoxide (0.032 g,0.34 mmol) and BINAP (0.01 g, 0.017 mmol) were added and the resultingreaction mixture was purged with argon gas for 5 min. followed by theaddition of Pd₂(dba)₃ (0.003 g, 0.003 mmol). The argon gas purging wascontinued for additional 15 min. before sealing the reaction vial. Thenthe reaction mixture was heated at 110° C. for 8 h. After completion ofthe reaction by TLC, reaction mass was filtered through celite and thefiltrate was evaporated, the residue was purified by combiflash byeluting with 0-40% ethyl acetate-hexane to afford the desired compound(0.025 g, 56%); LCMS: m/z=309.2 (M+H)⁺.

Step-iv: Synthesis of4-amino-N-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)amino)phenyl)benzamide

To a solution of 4-aminobenzoic acid (0.052 g, 0.78 mmol) in DMF (10 mL)was added HATU (0.15 g, 0.41 mmol) at 0° C. followed by DIPEA (0.12 mL,0.96 mmol) and finally addedN¹-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)benzene-1,3-diamine(0.1 g, 0.32 mmol). The reaction mass was stirred for 12 h at roomtemperature. The reaction mixture was quenched with ice-water anddiluted with ethyl acetate. The aqueous layer was separated andextracted with ethyl acetate (2×25 mL). The combined organic phase waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure and purified with silica gel column chromatography byeluting with 40% ethyl acetate-hexane to afford the title compound (0.07g, 50%). LCMS: m/z=428.2 (M+H)⁺.

Step-v: Synthesis of(E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)amino)phenyl)benzamide

(E)-4-bromobut-2-enoic acid (0.32 g, 1.99 mmol) was taken in DCM (20 mL)with catalytic amount of DMF followed by the addition of oxalyl chloride(0.27 g, 2.17 mmol). The reaction mass was stirred for 2 h, concentratedthe reaction mass under reduced pressure to residue. Re dissolved theresidue in DCM (2 mL) and was added at −5° C. to a mixture of4-amino-N-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)amino)phenyl)benzamide(0.42 g, 0.99 mmol) in acetonitrile (10 mL) and DIPEA (0.7 mL, 3.96mmol). The resulting reaction mixture was stirred for 10 minutes at −5°C. and after completion of the reaction, a solution of N,N-dimethylamine (2M in THF, 1.5 mL, 2.97 mmol) was added and thenallowed to stir at room temperature for 12 h. The reaction mixture wasquenched with saturated NaHCO₃ solution and diluted with DCM. Theaqueous layer was separated and extracted with DCM (2×25 mL). Thecombined organic phase was washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure and purified theresidue with silica gel column chromatography by eluting with 10%methanol-DCM to afford the title compound (0.12 g, 20%). LCMS: m/z=539.3(M+H)⁺.

Step-vi: Synthesis of(E)-N-(3-((1H-indazol-3-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide

Methanolic HCl (0.3 mL) was added to a solution of(E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)amino)phenyl)benzamide(0.12 g, 0.20 mmol) in DCM (4 mL) at room temperature and stirred for 2h, concentrated the reaction mass under reduced pressure. The residuewas dissolved in DCM and basified with NaHCO₃ solution. The separatedorganic phase was washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure and purified using prep. TLC byeluting with 10% methanol-DCM and triturated the resulting compound withether to afford the title compound (0.012 g, 16%). ¹HNMR (DMSO-d₆, 400MHz): δ 11.98 (s, 1H), 10.34 (s, 1H), 10.04 (s, 1H), 8.86 (s, 1H), 8.11(s, 1H), 7.97 (t, 3H), 7.78 (d, 2H), 7.47 (d, 1H), 7.32-7.38 (m, 2H),7.19 (t, 1H), 7.11 (d, 1H), 7.02 (t, 1H), 6.76-6.80 (m, 1H), 6.30-6.34(m, 1H), 3.12-3.14 (m, 2H), 2.08 (s, 6H); LCMS: m/z=455.3 (M+H)⁺; HPLC:95.93%, rt: 6.14 min.

Example-8: Synthesis ofN-(3′-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide(Compound-90)

Step-i: Synthesis of1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-amine

NaH (0.89 g, 22.3 mmol) was added lot wise to a stirred solution of3-amino indazole (2.5 g, 18.6 mmol) in DMF at 0° C., the reaction masswas stirred for 15 min followed by the addition of SEM chloride. Thereaction mass was stirred at ambient temperature for 2 h and wasquenched with ethyl acetate and ice cold water. The ethyl acetate layerwas separated, washed with water followed by brine, dried andconcentrated under reduced pressure, purified the crude by combiflash toafford the desired title compound (2.5 g, 50%) LCMS: m/z=264.1 (M+H)⁺.

Step-ii: Synthesis of2-(3-bromophenyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propanamide

To a solution of 2-(3-bromophenyl)propanoic acid (1.2 g, 5.2 mmol) inDCM (15 mL) was added oxalyl chloride (1.1 mL, 13.1 mmol) dropwise at 0°C. followed by the addition of one drop of DMF. The reaction mass wasstirred for 1 h and concentrated under reduced pressure. The resultingcrude residue was redissolved in DCM (5 mL) and added to a stirredsolution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-amine(1.38 g, 5.2 mmol) in pyridine (15 mL) and DCM (15 mL) at 0° C. Theresulting reaction mass was stirred at ambient temperature for 1 h. Thereaction mass was diluted with ethyl acetate and water. The separatedorganic layer was dried over anhydrous sodium sulphate and concentratedunder reduced pressure, the residue was purified by combiflash byeluting with 20% ethyl acetate-hexane system to afford the titlecompound (1.3 g, 54%) LCMS: m/z=474.4 (M+H)⁺.

Step-iii: Synthesis of2-(4′-amino-[1,1′-biphenyl]-3-yl)-N-(1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indazol-3-yl)propanamide

To a degassed solution of2-(3-bromophenyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propanamide(1.3 g, 2.7 mmol) andN-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide(0.92 g, 4.1 mmol) in 1,4-dioxane (15 mL) and water (4 mL), Cs₂CO₃ (2.72g, 8.3 mmol) was added. The reaction mass was stirred for 10 minutes anddegassed further for 10 minutes and added PdCl₂(dppf)₂.DCM (0.11 g, 0.13mmol). The reaction mass was heated for 12 h at 110° C. in a sealedtube. The reaction mass was cooled and diluted with water and ethylacetate. The separated organic layer was dried over anhydrous sodiumsulphate and concentrated under reduced pressure, purified the compoundby silica gel column chromatography by eluting with 40% ethylacetate-hexane system to afford the title compound (1 g, 78%) LCMS:m/z=487.4 (M+H)⁺.

Step-iv: Synthesis ofN-(3′-(1-oxo-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)amino)propan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide

TEA (0.34 mL, 2.4 mmol) was added to a solution of2-(4′-amino-[1,1′-biphenyl]-3-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propanamide(0.4 g, 0.8 mmol) in DCM (8 mL) at 0° C. The reaction mass was stirredfor 5 minutes and added acryloyl chloride (0.088 g, 0.9 mmol) in DCM (1mL). The resultant reaction mass was stirred for 20 minutes at 0° C.,quenched the reaction mass with ice cold water and DCM. The separatedorganic layer was washed with water followed by brine, dried andconcentrated under reduced pressure to afford the title compound (0.4 gcrude) LCMS: m/z=541.2 (M+H)⁺.

Step-v: Synthesis ofN-(3′-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide

TFA (5 mL) was slowly added to a stirred solution ofN-(3′-(1-oxo-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)amino)propan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide(0.4 g, 0.7 mmol) in dry DCM (5 mL) under argon atmosphere at 0° C. Theresulting reaction mixture was allowed to warm to room temperature andstirred for 12 h. After completion of the reaction, excess solvents wereremoved under reduced pressure. The resulting residue was stirred withaqueous NH₃ solution (10 mL) for 1 h. The solid separated was filteredand washed with ether and hexane and further purified by preparativeHPLC condition (Column: Zorbax C18 (21.2*150 mm), Mobile phase:Acetonitrile-water) to afford the title compound as free base (0.04 g,13%). ¹HNMR (DMSO-d₆, 400 MHz): δ 12.65 (s, 1H), 10.53 (s, 1H), 10.26(s, 1H), 7.78 (d, 2H), 7.73 (s, 1H), 7.65 (t, 3H), 7.54 (d, 1H),7.39-7.45 (m, 3H), 7.29 (t, 1H), 7.0 (t, 1H), 6.42-6.49 (m, 1H), 6.26(dd, 1H), 5.77 (dd, 1H), 4.03 (dd, 1H), 1.50 (d, 3H). LCMS: m/z=411.1(M+H)⁺; HPLC: 98.43%, rt: 3.95 min.

Example-9: Synthesis of(E)-N-(3′-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide(Compound-91)

Step-i: Synthesis of(E)-4-(dimethylamino)-N-(3′-(1-oxo-1-((1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indazol-3-yl)amino)propan-2-yl)-[1,1′-biphenyl]-4-yl)but-2-enamide

To a solution of (E)-4-bromobut-2-enoic acid (0.35 g, 2.1 mmol) in DCM(8 mL) was added oxalyl chloride (0.27 mL 2.3 mmol) drop wise at 0° C.followed by the addition of one drop of DMF, stirred the reaction massfor 1.5 h and concentrated under reduced pressure. The resulting cruderesidue redissolved in DCM (2 mL) and added to a stirred solution of2-(4′-amino-[1,1′-biphenyl]-3-yl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propanamide(0.51 g, 1 mmol) in DIPEA (0.94 mL, 5.3 mmol) and acetonitrile (10 mL)at 0° C. for 20 minutes followed by the addition of 2M N,N-dimethylaminesolution in THE (1.3 mL) at 0° C. The resulting reaction mass wasstirred at ambient temperature for 12 h. The reaction mass was dilutedwith DCM and water. The separated organic layer was dried over anhydroussodium sulphate and concentrated under reduced pressure, the residue waspurified by combiflash by eluting with 8% methanol-chloroform system toafford the title compound (0.3 g, 48%). LCMS: m/z=598.1 (M+H)⁺.

Step-ii: Synthesis of(E)-N-(3′-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide

TFA (5 mL) was slowly added to a stirred solution of(E)-4-(dimethylamino)-N-(3′-(1-oxo-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)amino)propan-2-yl)-[1,1′-biphenyl]-4-yl)but-2-enamide(0.3 g, 0.5 mmol) in dry DCM (5 mL) under argon atmosphere at 0° C. Theresulting reaction mixture was allowed to warm to room temperature andstirred for 12 h.

After completion of the reaction, excess solvents were removed underreduced pressure. The crude was purified by preparative HPLC condition(Column: Xbridge C18 (19*150 mm), Mobile phase: Ammoniumacetate-Acetonitrile-water) to afford the title compound as free base(0.01 g, 4.2%). ¹HNMR (DMSO-d₆, 400 MHz): δ 12.64 (s, 1H), 10.52 (s,1H), 10.17 (s, 1H), 7.75 (t, 3H), 7.62-7.67 (m, 4H), 7.53 (d, 1H),7.39-7.45 (m, 3H), 7.30 (t, 1H), 6.71-6.76 (m, 1H), 6.28 (d, 1H), 4.03(d, 1H), 3.06 (d, 2H), 2.18 (s, 6H), 1.51 (d, 3H). LCMS: m/z=468.1(M+H)⁺; HPLC: 90.40%, rt: 6.25 min.

Example-10: Synthesis of(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide(Compound-92)

Step-: Synthesis of2-(3-(6-aminopyrazin-2-yl)phenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide

To a degassed solution of tert-butyl5-cyclopropyl-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamido)-1H-pyrazole-1-carboxylate(1.5 g, 3.11 mmol) and 6-chloropyrazin-2-amine (0.32 g, 2.49 mmol) in1,4-dioxane (40 mL) and water (10 mL), Cs₂CO₃ (2.5 g, 7.69 mmol) wasadded. The reaction mass was stirred for 10 minutes and degassed furtherfor 10 min and added PdCl₂(dppf).DCM (0.17 g, 0.218 mmol). The reactionmass was heated for 12 h at 100° C. in a sealed tube. The reaction masswas cooled to room temperature and diluted with water and ethyl acetate.The separated organic layer was dried over anhydrous sodium sulphate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography by eluting with 15% ethyl acetate-hexane toafford the title compound (1 g, 50%) LCMS: m/z=349.2 (M+H)⁺.

Step-ii: Synthesis of(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide

(E)-4-bromobut-2-enoic acid (Intermediate-1d, 0.227 g, 1.31 mmol) wastaken in DCM (5 mL) with catalytic amount of DMF followed by theaddition of oxalyl chloride (0.121 g, 0.95 mmol). The reaction mass wasstirred for 1.5 h, concentrated the reaction mass under reduced pressureto residue. Re dissolved the reaction mass in DCM (2 mL) and was addedat 0° C. to a mixture of2-(3-(6-aminopyrazin-2-yl)phenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide(0.30 g, 0.86 mmol) in acetonitrile (5 mL) and DIPEA (0.37 mL, 2.16mmol). The resulting reaction mixture was stirred for 10 minutes at 0°C. and after completion of the reaction, a solution of pyrrolidine(0.086 g, 1.2 mmol) was added and then allowed to stir at roomtemperature for 12 h. The reaction mixture was quenched with saturatedNaHCO₃ solution and diluted with DCM. The aqueous layer was separatedand extracted with DCM (2×25 mL). The combined organic phase was washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure and purified the residue with silica gel column chromatographyby eluting with 10% methanol-DCM to afford the title compound (0.01 g,10%). ¹HNMR (DMSO-d₆, 400 MHz): δ 12.10 (s, 1H), 11.25 (s, 1H), 10.49(s, 1H), 9.93 (s, 1H), 9.39 (s, 1H), 8.95 (m, 1H), 8.09 (s, 1H),7.97-7.95 (d, 1H), 7.53-7.47 (m, 1H), 6.91-6.84 (m, 1H), 6.71-6.67 (d,1H), 6.11 (s, 1H), 4.09-4.06 (m, 2H), 3.94-3.93 (m, 1H), 3.61-3.55 (m,2H), 2.79-2.77 (m, 2H), 2.08-1.88 (m, 2H), 1.82-1.77 (m, 3H), 1.44-1.43(m, 3H), 0.88-0.85 (m, 2H), 0.64-0.62 (m, 2H), LCMS: m/z=485.2 (M+H)⁺,HPLC: 95.04%, rt: 7.07 min.

Example-11: Synthesis of(S,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide(Compound-93)

Step-i: Synthesis of tert-butyl(S)-3-(2-(3-bromophenyl)propanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate

(S)-2-(3-bromophenyl)propanoic acid (0.08 g, 0.34 mmol) (synthesiscarried out as described in reference WO2014/201073 A1) was taken in 2mL DCM at 0° C. with catalytic amount of DMF and added oxalyl chloride(0.42 g, 0.34 mmol), allowed to stir the reaction mass at roomtemperature for 1.5 h. The reaction mass was concentrated under vacuum,and the residue was dissolved in 2 mL of dry DCM and added to a cooledsolution of tert-butyl 3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate(0.078 g, 0.34 mmol) in 2 mL of DCM and TEA (0.086 g, 0.1 mL) at 0° C.The resultant reaction mass was stirred at room temperature for 1 h,after 1 h, the reaction mixture was diluted with DCM then washed withsaturated NaHCO₃ solution followed by brine solution. The organic layerwas dried over anhydrous sodium sulfate, concentrated under vacuum andpurified by silica gel column chromatography by eluting with 15% ethylacetate in hexane to afford the title compound (0.1 g, 53%). LCMS:m/z=436.1 (M+H)⁺.

Step-ii: Synthesis of tert-butyl(S)-5-cyclopropyl-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamido)-1H-pyrazole-1-carboxylate

To a degassed solution of tert-butyl(S)-3-(2-(3-bromophenyl)propanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate(0.1 g 0.23 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.087 g,0.34 mmol) in 1,4-dioxane (5 mL) was added potassium acetate (0.045 g,0.46 mmol). The reaction mass was allowed to stir for 10 minutes withdegassing at RT and added PdCl₂(dppf).DCM complex (0.010 g, 0.011 mmol).The reaction mass was heated for 12 h at 100° C. in a sealed tube,cooled the reaction mass and diluted with water and ethyl acetate. Theaqueous layer was separated and re-extracted with ethyl acetate (2×5mL). The combined organic layer was dried over anhydrous sodium sulfateand concentrated under vacuum. The crude was purified by silica gelcolumn chromatography by eluting with 20% ethyl acetate in hexane toafford the title compound (0.065 g, 58%), LCMS: m/z=482.2 (M+H)⁺.

Step-iii: Synthesis of (S,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide

To a degassed solution of tert-butyl(S)-5-cyclopropyl-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamido)-1H-pyrazole-1-carboxylate(0.065 g, 0.13 mmol) and(E)-N-(5-bromopyridin-2-yl)-4-morpholinobut-2-enamide (0.044 g, 0.13mmol) in 1,4-dioxane (2 mL) and water (0.1 mL) was added Cs₂CO₃ (0.084g, 0.26 mmol). The reaction mass was allowed to stir for 10 minutes withdegassing and added PdCl₂(dppf).DCM complex (0.005 g, 0.007 mmol),heated the reaction mass for 12 h at 100° C. in a sealed tube. Thereaction mass was cooled and diluted with water and ethyl acetate. Theaqueous layer was separated and re-extracted with ethyl acetate (2×5mL). The combined organic layer was dried over anhydrous sodium sulfateand concentrated under vacuum. The crude was purified by silica gelcolumn chromatography by eluting with 10% methanol in DCM (furtherpurified by Preparative HPLC, Column: GEMINI NX C18:21.2 mm*150 mm, A:0.01% Ammonia, B: ACN/MeOH) to afford the title compound (0.006 g, 8%).¹HNMR (CD3OD-d₆, 400 MHz): δ 8.57-8.56 (d, 1H), 8.26-8.24 (d, 1H),8.04-8.02 (m, 1H), 7.65 (s, 1H), 7.53-7.50 (m, 1H), 7.44-7.39 (m, 2H),7.00-6.93 (m, 1H), 6.43-6.39 (d, 1H), 6.13 (s, 1H), 3.89-3.88 (m, 1H),3.73-3.70 (m, 4H), 3.23-3.21 (m, 2H), 2.51-2.48 (m, 4H), 1.86-1.81 (m,1H), 1.54-1.39 (d, 3H), 0.94-0.92 (m, 2H), 0.68-0.62 (m, 2H); LCMS:m/z=501.1 (M+H)⁺; HPLC: 96.27%, rt: 5.88 min., Chiral HPLC: 90.84%, rt:8.87 min.

Example-12: Synthesis of(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1-(3-(6-(4-(pyrrolidin-1-yl)but-2-enamido)pyridin-3-yl)phenyl)cyclopropane-1-carboxamide(Compound-94)

Step-i: Synthesis of tert-butyl3-(1-(3-bromophenyl)cyclopropane-1-carboxamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate

To a solution of 1-(3-bromophenyl)cyclopropane-1-carboxylic acid (0.4 g,1.66 mmol) (synthesis carried out as described in references EP1206446B1; and WO2005/19161A1) in DMF (5 mL) was added HATU (0.94 g, 2.49 mmol)followed by DIPEA (0.86 mL, 4.98 mmol) at 0° C. and finally addedtert-butyl 3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate (0.37 g, 1.66mmol). The reaction mass was stirred for 15 h at room temperature. Thereaction mixture was quenched with ice-water and diluted with ethylacetate. The aqueous layer was separated and extracted with ethylacetate (2×25 mL). The combined organic phase was washed with brine,dried over Na₂SO₄, filtered and concentrated the crude residue waspurified by 100-200 silica gel column chromatography to afford desiredtitle compound (0.4 g, 54%). LCMS: m/z=448.0 (M+H)⁺.

Step-ii: Synthesis of tert-butyl5-cyclopropyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxamido)-1H-pyrazole-1-carboxylate

To a degassed solution of tert-butyl3-(1-(3-bromophenyl)cyclopropane-1-carboxamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate(0.2 g, 0.45 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.25 g,0.54 mmol) in 1,4-dioxane (10 mL) was added KOAc (0.13 g, 1.35 mmol).The reaction mass was stirred for 10 minutes and degassed further for 10minutes with argon and added PdCl₂(dppf).DCM (0.036 g, 0.045 mmol). Thereaction mass was heated for 15 h at 110° C. in a sealed tube. Then thereaction mass was cooled to room temperature and diluted with water andethyl acetate. The separated organic layer was dried over anhydroussodium sulphate and concentrated under vacuum and purified by silica gelcolumn chromatography by eluting with 15% ethyl acetate-hexane to affordthe title compound (0.2 g, crude) LCMS: m/z=494.2 (M+H)⁺.

Step-iii: Synthesis of(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1-(3-(6-(4-(pyrrolidin-1-yl)but-2-enamido)pyridin-3-yl)phenyl)cyclopropane-1-carboxamide

To a degassed solution of tert-butyl5-cyclopropyl-3-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxamido)-1H-pyrazole-1-carboxylate(0.2 g, 0.4 mmol) and(E)-N-(5-bromopyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide (0.1 g,0.33 mmol) (synthesised similar to intermediate 3-B) in 1,4-dioxane (10mL) and water (2 mL) Cs₂CO₃ (0.26 g, 0.81 mmol) was added. The reactionmass was stirred for 10 minutes and degassed further for 10 min withargon and added PdCl₂(dppf).DCM (0.033 g, 0.04 mmol). Then the reactionmass was heated for 15 h at 110° C. in a sealed tube. The reaction masswas cooled to room temperature and diluted with water and ethyl acetate.The separated organic layer was dried over anhydrous sodium sulphate andconcentrated under vacuum and purified by silica gel columnchromatography by eluting with 0-5% MeOH-DCM and further purified bypreparative HPLC (Method: A: 0.005% TFA in water, B: ACN-MeOH, Column:Kinetex 5μ (150 mm×19.0 mm) to afford the title compound (0.02 g, 10%).¹HNMR (DMSO-d₆, 400 MHz): δ 12.01 (s, 1H), 10.90 (s, 1H), 10.85 (brs,1H), 8.69-8.68 (d, 1H), 8.28-8.26 (m, 1H), 8.16-8.13 (m, 1H), 7.75 (s,1H), 7.67-7.65 (m, 1H), 7.50-7.42 (m, 2H), 6.88-6.81 (m, 1H), 6.49-6.45(m, 1H), 6.05 (s, 1H), 3.21-3.18 (m, 2H), 2.55-2.45 (m, 4H), 1.82-1.70(m, 1H), 1.70-1.68 (m, 4H), 1.45-1.42 (m, 2H), 1.16-1.12 (m, 2H),0.89-0.84 (m, 2H), 0.62-0.58 (m, 2H); LCMS: m/z=497.3 (M+H)⁺; HPLC:93.65%, rt: 4.52 min.

Example-13: Synthesis of(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-methyl-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide(Compound-95)

Step-i: Synthesis of tert-butyl3-(2-(3-bromophenyl)-2-methylpropanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate

To the solution of 2-(3-bromophenyl)-2-methylpropanoic acid (0.4 g, 1.66mmol)(synthesis carried out as described in reference US2008/194600A1)in DMF (5 mL) was added HATU (0.94 g, 2.49 mmol) followed by DIPEA (0.86mL, 4.98 mmol) at 0° C. and finally added tert-butyl3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate (0.37 g, 1.66 mmol).

The reaction mass was stirred for 15 h at room temperature. The reactionmixture was quenched with ice-water and diluted with ethyl acetate. Theaqueous layer was separated and extracted with ethyl acetate (2×25 mL).The combined organic phase was washed with brine, dried over Na₂SO₄,filtered and concentrated the crude residue was purified by 100-200silica gel column chromatography to afford desired compound (0.15 g,20%). LCMS: m/z=450.0 (M+H)⁺.

Step-ii: Synthesis of tert-butyl5-cyclopropyl-3-(2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamido)-1H-pyrazole-1-carboxylate

To a degassed solution of tert-butyl3-(2-(3-bromophenyl)-2-methylpropanamido)-5-cyclopropyl-1H-pyrazole-1-carboxylate(0.15 g, 0.45 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.1 g, 0.4mmol) in 1,4-dioxane (10 mL) was added KOAc (0.1 g, 1.0 mmol). Thereaction mass was stirred for 10 minutes and degassed further for 10minutes with argon and added PdCl₂(dppf).DCM (0.027 g, 0.033 mmol). Thereaction mass was heated for 15 h at 110° C. in a sealed tube. Cooledthe reaction mass and diluted with water and ethyl acetate. Theseparated organic layer was dried over anhydrous sodium sulphate andconcentrated under vacuum and purified by silica gel columnchromatography by eluting with 15% ethyl acetate-hexane to afford thetitle compound (0.15 g, 92%) LCMS: m/z=496.3 (M+H)⁺.

Step-iii: Synthesis of(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-methyl-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide

To a degassed solution of tert-butyl5-cyclopropyl-3-(2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamido)-1H-pyrazole-1-carboxylate(0.14 g, 0.28 mmol) and(E)-N-(5-bromopyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide (0.09 g,0.28 mmol) in 1,4-dioxane (10 mL) and water (2 mL) added Cs₂CO₃ (0.17 g,0.56 mmol). The reaction mass was stirred for 10 minutes and degassedfurther for 10 min with argon and added PdCl₂(dppf).DCM (0.023 g, 0.028mmol), then heated for 15 h at 110° C. in a sealed tube. The reactionmass was cooled to room temperature and diluted with water and ethylacetate. The separated organic layer was dried over anhydrous sodiumsulphate and concentrated under vacuum and the residue was purified bysilica gel column chromatography by eluting with 0-5% MeOH-DCM andfurther purified by preparative HPLC (Method: A: 0.005% TFA in water, B:ACN-MeOH, Column: Kinetex 5μ (150 mm×19.0 mm) to afford the titlecompound (0.004 g, 2.85%). ¹HNMR (DMSO-d₆, 400 MHz): δ 11.05 (s, 1H),9.89 (brs, 1H), 9.49 (s, 1H), 8.68-8.67 (m, 1H), 8.28-8.26 (m, 1H),8.15-8.12 (m, 1H), 7.65 (s, 1H), 7.659-7.57 (m, 1H), 7.46-7.42 (m, 1H),7.34-7.32 (m, 1H), 6.85-6.79 (m, 1H), 6.66-6.62 (m, 1H), 6.12 (s, 1H),3.07-3.05 (m, 2H), 2.5 (s, 4H), 2.00-1.80 (m, 5H), 1.60 (s, 6H),0.90-0.87 (m, 2H), 0.64-0.60 (m, 2H); LCMS: m/z=499.3 (M+H)⁺; HPLC:95.03%, rt: 6.16 min.

Although the present invention has been illustrated by certain of thepreceding examples, it is not to be construed as being limited thereby;but rather, the present invention encompasses the generic area ashereinbefore disclosed. Various modifications and embodiments can bemade without departing from the spirit and scope thereof. For example,the compounds in the table-4 below which can be prepared by followingsimilar procedure as described in above Schemes/Examples with suitablemodifications known to the one ordinary skilled in the art are alsoincluded in the scope of the present invention:

TABLE 4 Compound. No. Structure  96.

 97.

 98.

 99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

and 143.

Biochemical Assay for CDK7:

The ability of compounds to inhibit CDK7 kinase activity was tested in aTR-FRET assay using 5 nM of CDK7/CycH/MNAT1 obtained from Invitrogen,USA. Test compounds were pre-incubated with the kinase at roomtemperature for 60 min. After the incubation, substrate mix [100 nMUltra-light MBP (Perkin Elmer, USA) and 1 mM ATP (Sigma)] was added. Theabove reaction was stopped by the addition of 40 mM EDTA after 60minutes of kinase reaction. 1 nM Eu-labelled antiphospho-MBP antibody[Perkin Elmer, USA] was added, mixed well and the fluorescence emissionat 615 nm and 665 nm [excitation at 340 nm] was measured. The final DMSOconcentration in the assay was 1%. For IC₅₀ determination, appropriateconcentrations were made by ⅓^(rd) serial dilutions of 10 mM DMSO stocksolution of test compound. All the fluorescence measurements were madein a Victor 3 Multilabel Counter [Perkin Elmer, USA]. The IC₅₀ wasdetermined by fitting the dose response data to sigmoidal curve fittingequation using GraphPad Prism software V5. To identify compounds thatinhibit CDK7 irreversibly, time depended inhibition studies were carriedby pre-incubating compound with the enzyme at three time points (20, 60and 180 min) and carrying out assay as described above.

The compounds were screened by the above mentioned assay procedure. The% inhibition at 10 μM concentration and the IC₅₀ values of the compoundsare summarized in the table-5 below wherein “+++” refers to an IC₅₀value less than 0.025 μM, “++” refers to IC₅₀ value in range of 0.025 μMto 0.1 μM and “+” refers to an IC₅₀ value greater than 0.1 μM.

TABLE 5 % inhibition and IC₅₀ values Compound % inhibition IC₅₀ No. @ 10μM (μM) 1  92% ++ 2  69% + 3  99% ++ 4  95% + 5  80% + 6  0% − 7  84% +8  92% + 9  60% + 10  99% +++ 11  75% + 12  98% +++ 13  97% ++ 14  95% +15  93% +++ 16  95% ++ 17  80% + 18  95% + 19  97% ++ 20 100% +++ 21 89% + 22  97% +++ 23  98% ++ 24  96% ++ 25  97% ++ 26  96% +++ 27  98%+++ 28  96% ++ 29  97% +++ 30  28% + 31 100% +++ 32 100% +++ 33  97% ++34  88% + 35  86% + 36  98% +++ 37  67% + 38  94% + 39  84% + 40 100%+++ 41  90% + 42  98% +++ 43  99% +++ 44  99% +++ 45  89% +++ 46  95%+++ 47  91% +++ 48  90% ++ 49  89% +++ 50  94% +++ 51  90% + 52  91% +++53 100% +++ 54  78% +++ 55  95% +++ 56  96% +++ 57  98% +++ 58  90% + 59 99% ++ 60  99% ++ 61  92% + 62  81% + 63  98% ++ 64  94% ++ 65  94% +66  88% + 67  79% + 68  95% +++ 69  87% ++ 70  81% ++ 71  81% + 72  98%+++ 73  91% + 74  79% + 75  78% + 76  98% +++ 77  98% ++ 78 100% ++ 79102% +++ 80  95% ++ 81 100% ++ 82  99% ++ 83  62% + 84  88% + 85  74% +86  48% − 87  89% + 88  62% + 89  45% − 90  83% + 91  84% + 92  86% ++93 100% +++ 94  85% + 95  71% +

1. A compound of formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein, ring A is cycloalkyl, aryl, heteroaryl or heterocyclyl; ring Bis aryl, cycloalkyl, heterocyclyl or absent; R₁ is hydrogen or alkyl; R₂is hydrogen, alkyl or cycloalkyl; R₃ is hydrogen, alkyl or heteroaryl;alternatively, R₂ together with R₁ or R₃ along with the ring atoms towhich they are attached forms a 5-7 membered ring; R₄ at each occurrenceis halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano or haloalkyl; R₅

wherein R₅′ is hydrogen, halo, alkyl, alkoxy, alkoxyalkyl or—(CH₂)₁₋₃—NR_(a)R_(b); R₅″ is H or alkyl; R_(a) and R_(b) are eachindependently hydrogen, alkyl, alkoxy or alkoxyalkyl; alternatively,R_(a) and R_(b) together with the nitrogen atom to which they areattached form an optionally substituted ring containing 0-2 additionalheteroatoms independently selected from N, O or S; wherein the optionalsubstituent is one or more halo, alkyl, acyl, hydroxy, cyano,cyanoalkyl, haloalkyl, alkoxy, alkoxyalkyl, —COOH or —COO-alkyl; R₆ ateach occurrence is halo, alkyl, hydroxy, alkoxy, amino, nitro, cyano orhaloalkyl; L₁ is *—CR_(c)R_(d)—C(O)—, *—NR_(c)C(O)— or absent; wherein *is point of attachment with ring A; R_(c) and R_(d) independently arehydrogen, alkyl or haloalkyl; alternatively, R_(c) and R_(d) togetherwith the carbon to which they are attached form a cycloalkyl ring; Re ishydrogen or alkyl; L₂ is —C(O)NH—, —C(O)O— or absent; m is 0, 1 or 2; pis 0 or 1; and q is 0 to
 3. 2-24. (canceled)
 25. A method of treating adisease mediated by selective transcriptional CDKs in a subjectcomprising administering to the subject in need thereof atherapeutically effective amount of a compound according to claim 1,wherein the disease is a cancer selected from the group consisting of acarcinoma, including that of the breast, liver, lung, colon, kidney,bladder, including small cell lung cancer, non-small cell lung cancer,head and neck, thyroid, esophagus, stomach, pancreas, ovary, gallbladder, cervix, prostate and skin, including squamous cell carcinoma;hematopoietic tumors of lymphoid lineage, including leukemia, acutelymphoblastic leukemia, acute lymphocytic leukemia, Hodgkins lymphoma,non-Hodgkins lymphoma, B-cell lymphoma, T-cell lymphoma, hairy celllymphoma, myeloma, mantle cell lymphoma and Burkett's lymphoma;hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia; tumors of masenchymal origin, including fibrosarcoma andrhabdomyosarcoma; tumors of the central and peripheral nervous system,including astrocytoma, neuroblastoma, glioma and schwannomas; and othertumors, including seminoma, melanoma, osteosarcoma, teratocarcinoma,keratoctanthoma, xenoderoma pigmentosum, thyroid follicular cancer andKaposi's sarcoma. 26-31. (canceled)
 32. A process for preparing acompound of formula (IC-1),

the process comprising the steps: a) reacting a compound of formula (a)with a compound of formula (b) to afford a compound of formula (c):

b) reacting the compound of formula (c) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to afford acompound of formula (h):

and c) coupling the compound of formula (h) with a compound of formula(i) to afford a compound of formula (IC-1):

wherein, ring A is 1,3-phenylene; ring B is aryl or heterocyclyl; R₁ ishydrogen; R₂ is hydrogen, alkyl or cycloalkyl; R₃ is hydrogen or alkyl;alternatively, R₂ together with R₃ along with the ring atoms to whichthey are attached forms a 5-7 membered ring; R₄ at each occurrence ishalo, alkyl or haloalkyl; R₅ is

wherein R₅′ is hydrogen, alkyl, alkoxyalkyl or —(CH₂)₁₋₃—NR_(a)R_(b);R₅″ is H or alkyl; R_(a) and R_(b) are each independently hydrogen,alkyl, alkoxy or alkoxyalkyl; alternatively, R_(a) and R_(b) togetherwith the nitrogen atom to which they are attached form an optionallysubstituted ring containing 0-2 additional heteroatoms that areindependently N, O or S; wherein the optional substituent is one or morehalo, alkyl, cyano, cyanoalkyl, alkoxy, alkoxyalkyl, —COOH or —COO—alkyl; R₆ at each occurrence is halo, alkyl, alkoxy or haloalkyl; L₁ is*—CR_(c)R_(d)—C(O)— or absent; wherein * is point of attachment withphenyl ring; R_(c) and R_(d) independently are hydrogen or alkyl;alternatively, R_(c) and R_(d) together with the carbon atom to whichthey are attached form a cycloalkyl ring; m is 0, 1 or 2; p is 1; and qis 0 to
 3. 33. The process of claim 32, wherein the compound of formula(I) is a compound of formula (ID):


34. The process of claim 32, wherein the compound of formula (I) is acompound of formula (IF):

wherein, R₃ is hydrogen, R₅ is,

wherein R₅′ is hydrogen, alkyl, alkoxyalkyl or —(CH₂)₁₋₃—NR_(a)R_(b);R₅″ is H or alkyl; L₁ is *—CR_(c)R_(d)—C(O)—; wherein * is point ofattachment with phenyl ring; and m is
 0. 35. The process of claim 32,wherein ring B is monocyclic or bicyclic, aryl or heteroaryl.
 36. Theprocess of claim 32, wherein R₂ is cycloalkyl.


37. The process of claim 32, wherein R₅ is
 0. 38. The process of claim37, wherein R₅′ is —(CH₂)₁₋₃—NR_(a)R_(b); wherein R_(a) and R_(b) areeach independently hydrogen or alkyl; alternatively, R_(a) and R_(b)together with the nitrogen atom to which they are attached to form anoptionally substituted ring containing 0-2 additional heteroatoms thatare independently N, O or S; wherein the optional substituent is one ormore halo, alkyl or alkoxy.
 39. The process of claim 38, wherein R_(a)and R_(b) together with the nitrogen atom to which they are attachedform an optionally substituted heterocyclic ring containing 0-2additional heteroatoms that are independently O, S or N.
 40. The processof claim 32, wherein L₁ is *—CR_(c)R_(d)—C(O)—; wherein * is the pointof attachment with phenyl ring.
 41. The process of claim 32, wherein thecompound of formula (I) is a compound selected from: Compound No. IUPACname 1.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 2.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide (Isomer-1 of compound-1);3.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide (Isomer-2 of compound-1);4.(E)-N-(5′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2′-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 5.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-4′-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 7.(E)-N-(3′-(2-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 8.(E)-4-(dimethylamino)-N-(3′-(1-((5-ethyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)but-2-enamide; 9.(E)-N-(3′-(1-((5-(tert-butyl)-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 10.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide; 11.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide (Isomer-1 ofcompound-10); 12.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide (Isomer-2 ofcompound-10); 13.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxobutan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 14.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 15.(E)-N-(3′-(1-((5-cyclobutyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 16.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)-4-(dimethylamino)but-2-enamide; 17.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 18.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide; 19.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)acrylamide; 20.N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide; 21.N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide (Isomer-1 of compound-20); 22.N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide (Isomer-2 of compound-20); 23.N-(5′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2′,3-difluoro-[1,1′-biphenyl]-4-yl)acrylamide; 24.N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)acrylamide; 25.2-(4′-acrylamido-3′-fluoro-[1,1′-biphenyl]-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-methylbutanamide; 26.2-(3-(5-acrylamidopyridin-2-yl)phenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)butanamide; 27.2-(4′-acrylamido-3′-fluoro-[1,1′-biphenyl]-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)butanamide; 28.(E)-N-(3′-(1-((5-cyclopentyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 29.(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)indolin-5-yl)phenyl)propanamide; 30.N-(3′-(1-((5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide; 31.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxobutan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 32.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(diethylamino)but-2-enamide; 33.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(pyrrolidin-1-yl)but-2-enamide; 34.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-morpholinobut-2-enamide; 35.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)-4-morpholinobut-2-enamide; 36.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-3-yl)-4-(dimethylamino)but-2-enamide; 37.(E)-4-((6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)amino)-N,N-dimethylbut-2-enamide; 38.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-2-fluoropyridin-3-yl)-4-(dimethylamino)but-2-enamide; 39.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)-4-(piperidin-1-yl)but-2-enamide; 40.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(piperidin-1-yl)but-2-enamide; 41.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-methoxybut-2-enamide; 42.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide; 43.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 44.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide; 45.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(3-fluoropyrrolidin-1-yl)but-2-enamide; 46.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide;47. (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide(Isomer-1 of compound-46); 48.E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide(Isomer-2 of compound-46); 49.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((R)-3-fluoropyrrolidin-1-yl)but-2-enamide 50.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((R)-3-fluoropyrrolidin-1-yl)but-2-enamide(Isomer-1 of compound-49); 51.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((R)-3-fluoropyrrolidin-1-yl)but-2-enamide(Isomer-2 of compound-49); 52.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide; 53.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide (Isomer-1 ofcompound-52); 54.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide (Isomer-2 ofcompound-52); 55.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(diethylamino)but-2-enamide; 56.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide; 57.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(3-fluoropiperidin-1-yl)but-2-enamide; 58.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-2-fluoropyridin-3-yl)-4-morpholinobut-2-enamide; 59.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-6-fluoropyridin-2-yl)-4-morpholinobut-2-enamide; 60.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)-4-morpholinobut-2-enamide; 61.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-3-yl)-4-morpholinobut-2-enamide; 62.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(methoxy(methyl)amino)but-2-enamide; 63.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-3-fluoropyridin-2-yl)-4-morpholinobut-2-enamide; 64.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-2-fluoropyridin-3-yl)-4-(3-fluoropyrrolidin-1-yl)but-2-enamide; 65.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-methoxy- [1,1′-biphenyl]-4-yl)acrylamide;66.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-methyl-[1,1′-biphenyl]-4-yl)acrylamide; 67.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3,5-dimethyl-[1,1′-biphenyl]-4-yl)acrylamide; 68.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-enamide;69. (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(1H-imidazol-1-yl)but-2-enamide; 70.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)but-2-enamide; 71.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)but-2-enamide(Isomer-1 of compound-70); 72.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)but-2-enamide(Isomer-2 of compound-70); 73.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2-methoxy-[1,1′-biphenyl]-4-yl)acrylamide; 74.N-((5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)methyl)acrylamide; 75.N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-2-methyl-[1,1′-biphenyl]-4-yl)acrylamide; 76.2-(3-(1-acryloylindolin-5-yl)phenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide; 77.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-((2S,4S)-4-fluoro-2-(methoxymethyl)pyrrolidin-1-yl)but-2-enamide; 78.(E)-4-(3-cyanopyrrolidin-1-yl)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 79.N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)acrylamide; 80.(E)-N-(3′-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4-((S)-3-fluoropyrrolidin-1-yl)but-2-enamide; 81.methyl((E)-4-((5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)amino)-4-oxobut-2-en-1-yl)-L-prolinate; 82.(E)-4-((S)-2-(cyanomethyl)pyrrolidin-1-yl)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 83.4-acrylamido-N-(3-((5-ethyl-1H-pyrazol-3-yl)amino)phenyl)benzamide; 84.(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanamide; 85.(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)phenyl)propanamide; 86.N-(3′-(2-((5-methyl-1H-pyrazol-3-yl)amino)-2-oxoethyl)-[1,1′-biphenyl]-4-yl)acrylamide; 87.N-(3′-(1-((5-ethyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide; 88.N-(3′-(1-((5-(tert-butyl)-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide; 89.(E)-N-(3-((1H-indazol-3-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide; 90.N-(3′-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)acrylamide; 91.(E)-N-(3′-(1-((1H-indazol-3-yl)amino)-1-oxopropan-2-yl)-[1,1′-biphenyl]-4-yl)-4-(dimethylamino)but-2-enamide; 92.(E)-N-(6-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide; 93.(S,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide; 94.(E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1-(3-(6-(4-(pyrrolidin-1-yl)but-2-enamido)pyridin-3-yl)phenyl)cyclopropane-1-carboxamide; and 95.(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-2-methyl-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide;


42. The process of claim 32, comprising: a) reacting a compound offormula (1a) with a compound of formula (1-B) to form a compound offormula (1b):

b) reacting the compound of formula (1b) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to afford acompound of formula (2a):

and c) coupling the compound of formula (2a) with a compound of formula(3-B) to afford(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide:


43. The process of claim 32, comprising: a) reacting a compound offormula (1a) with a compound of the formula:

to form a compound of the formula;

b) reacting the compound of the formula:

with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) toafford a compound of the formula:

and c) coupling the compound of the formula

with a compound of formula (3-B) to afford(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1l-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide:


44. The process of claim 42, wherein(E)-N-(5-(3-(1-((5-cyclopropyl-H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamideis racemic.
 45. The process of claim 42, wherein(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamideis the (S)-enantiomer.
 46. The process of claim 42, wherein(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamideis the (R)-enantiomer.
 47. The process of claim 43, wherein(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamideis racemic.
 48. The process of claim 43, wherein(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamideis an enantiomer.
 49. The process of claim 32, wherein the step a) iscarried out in presence of dichloromethane solvent, catalytic amount ofdimethylformamide and oxalyl chloride, followed by reacting the obtainedacid chloride with tert-butyl3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate in presence of pyridinesolvent or DCM/TEA.
 50. The process of claim 32, wherein step b) iscarried out in presence of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane),1,4-dioxane, potassium acetate and PdCl₂(dppf) DCM complex orPdCl₂(PPh₃)₂.
 51. The process of claim 32, wherein step c) is carriedout in presence of(E)-N-(5-bromopyridin-2-yl)-4-morpholinobut-2-enamide, 1,4-dioxane,water, Cs₂CO₃ and PdCl₂(dppf).DCM complex or PdCl₂(PPh₃)₂.